US7807701B2 - Dibenzylamine compounds and pharmaceutical use thereof - Google Patents

Dibenzylamine compounds and pharmaceutical use thereof Download PDF

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US7807701B2
US7807701B2 US11/939,359 US93935907A US7807701B2 US 7807701 B2 US7807701 B2 US 7807701B2 US 93935907 A US93935907 A US 93935907A US 7807701 B2 US7807701 B2 US 7807701B2
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hydrochloride
methyl
ethylamino
amino
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US20080146620A1 (en
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Kimiya Maeda
Hironobu Nagamori
Hiroshi Nakamura
Hisashi Shinkai
Yasunori Suzuki
Daisuke Takahashi
Toshio Taniguchi
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Japan Tobacco Inc
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Japan Tobacco Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a novel CETP activity inhibitor, particularly a therapeutic agent or a prophylactic agent of arteriosclerosis or hyperlipidemia.
  • CETP cholesterol ester transfer protein
  • CETP is produced in the organs such as liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle, heart muscle and the like, and produced in cells of the cell types of human monocyte-derived macrophage, B lymphocyte, fat cell, small intestinal epithelial cell, CaCo2 cell, hepatocyte (exemplified by human liver cancer cell-derived cell line, HepG2 cells) and the like.
  • hepatocyte exemplified by human liver cancer cell-derived cell line, HepG2 cells
  • it is present in cerebrospinal fluid and semen, and its presence has been confirmed in culture media of human neuroblastoma and neuroglioma cells, choroid plexus of sheep and the like.
  • CETP is involved in the metabolism of any lipoprotein in living organisms, and has a major role in the reverse cholesterol transfer system. Namely, CETP has drawn attention as a mechanism for preventing accumulation of cholesterol in peripheral cells and preventing arteriosclerosis.
  • HDL high-density lipoprotein
  • a number of epidemiological researches have shown that a decrease in CE (cholesteryl ester) of HDL in blood is one of the risk factors of coronary artery diseases.
  • CETP activity varies depending on the animal species, wherein arteriosclerosis due to cholesterol-loading is hardly induced in animals with lower activity, and in reverse, easily induced in animals with higher activity, and that hyper-HDL-emia and hypo-LDL (low density lipoprotein)-emia are induced in the case of CETP deficiency, thus rendering the development of arteriosclerosis difficult, which in turn led to the recognition of the significance of blood HDL, as well as significance of CETP that mediates transfer of CE in HDL into blood LDL.
  • arteriosclerosis due to cholesterol-loading is hardly induced in animals with lower activity, and in reverse, easily induced in animals with higher activity, and that hyper-HDL-emia and hypo-LDL (low density lipoprotein)-emia are induced in the case of CETP deficiency, thus rendering the development of arteriosclerosis difficult, which in turn led to the recognition of the significance of blood HDL, as well as significance of CETP that mediates transfer of CE in HDL into blood LDL.
  • VLDL very low density lipoprotein
  • LPL lipoprotein lipase
  • HTGL hepatic triglyceride lipase
  • IDL intermediate density lipoprotein
  • FC accumulated in the peripheral tissues is drawn by HDL, further esterified on HDL by the action of LCAT (lecithin-cholesterol acyltransferase) to form CE, and transferred to the hydrophobic core part of HDL, whereby HDL matures into spheric HDL particles.
  • CE in HDL is transferred by CETP present in blood to apoB-containing lipoproteins such as VLDL, IDL, LDL and the like, and in return, TG is transferred to HDL at a molar ratio of 1:1.
  • CE transferred to apoB-containing lipoprotein is taken up by the liver via LDL receptor in the liver, thereby indirectly transferring cholesterol to the liver.
  • HDL takes up apoprotein E secreted from macrophage and the like to become apoprotein E-containing HDL rich in CE, and then is directly taken up by the liver via LDL receptor or remnant receptor.
  • HDL particles are not taken up by the liver and only CE in HDL is selectively taken up by hepatocytes.
  • HDL particles are taken up by hepatocytes via what is called an HDL receptor in the liver.
  • WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETP activity inhibitors. However, this publication does not contain any description suggesting the compound of the present invention.
  • JP-B-45-11132, JP-B-45-2892, JP-B-45-2891, JP-B-45-2731 and JP-B-45-2730 disclose mercaptoanilides substituted by higher fatty acid such as o-isostearoylaminothiophenol and the like, as a compound having an action to prevent arteriosclerosis.
  • these publications only mention the presence of an effect to prevent arteriosclerosis and lack description of Experimental Example that support the effect, much less a description of inhibition of CETP activity.
  • no description is found that suggests the compound of the present invention.
  • JP-T-2001-512416 discloses a biaryl compound that inhibits CETP.
  • this publication has no description that suggests the compound of the present invention.
  • JP-A-2001-106666 and WO01/10825 disclose carbamate derivatives characterized in that phenyl group has an oxime ether group.
  • the compounds of these publications are compounds useful as antimicrobial agents for agriculture or gardening, and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO00/69810 discloses compounds such as 3-(4- ⁇ [N-[3-(2,6-dichlorophenyl)acryloyl]-N-(4-tert-butylbenzyl)amino]methyl ⁇ benzoylamino)propionic acid and the like.
  • the compound of this publication is useful as a glucagon antagonist, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO99/67204 discloses compounds such as 1-[N-(4-chlorobenzyl)-N—(N,N-dimethylcarbamoyl)aminomethyl]-4-guanidinomethylbenzene and the like.
  • the compound of this publication is useful as an analgesic, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO99/44987 and U.S. Pat. No. 6,218,426 disclose compounds such as N-(4-tert-butylbenzyl)-N-[4-(guanidinomethyl)benzyl]benzamide and the like useful as a gonadotropin-releasing hormone antagonist/agonist.
  • this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO97/24328 discloses 2-amino-heterocyclic compounds such as N,N-bis(2,4-dimethoxybenzyl)-N′-(4-methoxyphenyl)urea and the like.
  • the compound of this publication is useful as a leukotriene synthesis inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO96/10559 discloses urea derivatives such as 1-benzyl-1-[3-(pyrazol-3-yl)benzyl]-3-(2,4,6-trimethylphenyl)urea and the like.
  • the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • U.S. Pat. No. 4,623,662 discloses that urea compounds such as 1-benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea and the like are useful as acyl-CoA:cholesterol acyltransferase inhibitors.
  • this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • U.S. Pat. No. 4,473,579 discloses urea compounds such as 1,1-dibenzyl-3-(2,4-dimethylphenyl)-3-phenylurea and the like.
  • the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • U.S. Pat. No. 4,122,255, U.S. Pat. No. 4,064,125, U.S. Pat. No. 4,151,354 and U.S. Pat. No. 4,127,606 disclose compounds such as N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]-3-phenyl-N-(phenylmethyl)-2-propenamide and the like.
  • the compounds of these publications are useful as antiinflammatory agents and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • WO99/18066 discloses amide carboxylic acid compounds such as ethyl 2-butyl-3-[4-[2-[N-benzyl-(4-pyridin-2-yl)amino]ethoxy]phenyl]propionate and the like having useful lipid-lowering action and the like.
  • this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
  • this publication lacks a disclosure of a structure such as the compound of the present invention, or even a description suggestive thereof.
  • R 2 and R 3 form a hetero ring or cycloalkenyl in combination
  • the compound is structurally similar to the present invention.
  • this invention lacks a concrete disclosure (Example) of ring B as shown in the present invention.
  • this invention is distinct from the present invention in that the invention always has R 1 (haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkenyloxyallyl).
  • the present invention aims at providing a novel compound that selectively inhibits the activity of CETP.
  • the present invention also aims at providing a compound useful as a prophylactic or therapeutic agent of arteriosclerosis or hyperlipidemia, which increases HDL cholesterol and simultaneously decreases LDL cholesterol and triglyceride by selectively inhibiting the activity of CETP, and which is free of a CYP inhibitory effect.
  • R 60 and R 61 are as defined above or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • A is —N(R 7 )(R 8 ) (wherein R 7 and R 8 are as defined in the above-mentioned [1]) or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • R 7 is a C 1-6 allyl group or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • halogen atom is a chlorine atom, a bromine atom, a fluorine atom and the like.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 60 , R 61 or R 62 it is preferably a chlorine atom or a fluorine atom, and a preferable halogen atom as a substituent for the C 4-10 cycloalkylalkyl group for R 7 , R 8 , R 11 , R 12 or R 13 is chlorine atom or fluorine atom.
  • the “C 2-6 alkenyl group” is a straight chain or optionally branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 1-isopropylvin
  • the “C 1-6 alkyl group” is a straight chain or optionally branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and the like, preferably a straight chain or optionally branched alkyl group having 1 to 4 carbon atoms. Particularly preferred are methyl group, ethyl group and isopropyl group.
  • R 20 and R 21 are each preferably a methyl group.
  • R 6 , R 60 , R 61 or R 62 it is preferably a methyl group or an ethyl group
  • R 7 , R 8 , R 11 , R 12 or R 13 it is preferably an ethyl group, a propyl group or a butyl group
  • R 9 or R 10 it is preferably a methyl group or an ethyl group.
  • a preferable C 1-6 allyl group as a substituent for the C 4-10 cycloalkylalkyl group for R 7 , R 8 , R 11 , R 12 or R 13 is a methyl group or an ethyl group.
  • R 14 it is preferably a methyl group or an ethyl group.
  • C 1-6 alkyl group optionally substituted by halogen atoms is the aforementioned C 1-6 alkyl group optionally substituted by the aforementioned halogen atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, trifluoromethyl group, 1- or 2-chloroethyl group, 1- or 2-bromoethyl group, 1- or 2-fluoroethyl group, 1-, 2- or 3-chloropropyl group, 1-, 2- or 3-bromopropyl group, 1-, 2- or 3-fluoropropyl group, 1-, 2-, 3- or 4-chlorobutyl group, 1-, 2-, 3- or 4-bromobutyl group, 1-, 2-,
  • the “C 1-6 alkoxy group” means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group and hexyloxy group.
  • Particularly preferred are methoxy group and ethoxy group.
  • R 6 , R 60 , R 61 or R 62 it is preferably a methoxy group, and a preferable C 1-6 alkoxy group as a substituent for the C 4-10 cycloalkylalkyl group for R 7 , R 8 , R 11 , R 12 or R 13 is a methoxy group or an ethoxy group.
  • the “C 1-6 alkoxy group optionally substituted by halogen atoms” is the aforementioned C 1-6 alkoxy group optionally substituted by the aforementioned halogen atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group, hexyloxy group, trifluoromethoxy group, 1- or 2-chloroethoxy group, 1- or 2-bromoethoxy group, 1- or 2-fluoroethoxy group, 1-, 2- or 3-chloropropoxy group, 1-, 2- or 3-bromopropoxy group, 1-, 2- or 3-fluoropropoxy group, 1-, 2-, 3- or 4-chlorobutoxy group, 1-, 2-, 3- or 4-bromobutoxy group, 1-, 2-, 3- or 4-fluorobutoxy group and the like.
  • Preferred are methoxy group, ethoxy group and trifluoromethoxy
  • C 1-6 allylthio group optionally substituted by halogen atoms is one wherein the C 1-6 allylthio group is optionally substituted by the aforementioned halogen atoms, which is exemplified by methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, tert-butylthio group, pentylthio group, tert-pentylthio group, hexylthio group, trifluoromethylthio group, 1- or 2-chloroethylthio group, 1- or 2-bromoethylthio group, 1- or 2-fluoroethylthio group, 1-, 2- or 3-chloropropylthio group, 1-, 2- or 3-bromopropylthio group, 1-, 2- or 3-fluoropropylthio group, 1-, 2-, 3- or 4-chlorobutylthio group, 1-,
  • the “C 4-10 cycloalkylalkyl group” is a C 1-3 alkyl group substituted by C 3-7 cycloalkyl group.
  • the “C 3-7 cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, which is exemplified by cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group.
  • Preferred is cycloalkyl group having 3 to 6 carbon atoms, which is specifically cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.
  • C 1-3 alkyl group means a straight chain or optionally branched alkyl group having 1 to 3 carbon atoms, which is exemplified by methyl group, ethyl group, propyl group and isopropyl group. Preferred are methyl group, ethyl group and propyl group.
  • C 4-10 cycloalkylalkyl group examples include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclopentylethyl group (1- or 2-(cyclopentyl)ethyl group), cyclohexylethyl group (1- or 2-(cyclohexyl)ethyl group), cyclopentylpropyl group (1-, 2- or 3-(cyclopentyl)propyl group) and cyclohexylpropyl group (1-, 2- or 3-(cyclohexyl)propyl group).
  • cycloalkylalkyl group preferably having 3 to 7 carbon atoms, which is specifically cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group or cyclohexylmethyl group.
  • a preferable C 4-10 cycloalkylalkyl group for R 7 , R 8 , R 11 , R 12 or R 13 is cyclopentylmethyl group, cyclohexylmethyl group or 2-(cyclopentyl)ethyl group.
  • acyl group includes alkylcarbonyl groups such as acetyl group, propionyl group, butyryl group, pivaloyl group and the like; and arylcarbonyl groups such as benzoyl group, naphthoyl and the like. Preferred is acetyl group.
  • R 6 , R 60 , R 61 or R 62 it is preferably an acetyl group, a preferable acyl group as a substituent for the C 4-10 cycloalkylalkyl group for R 7 , R 8 , R 11 , R 12 or R 13 is acetyl group.
  • the “aryl group” is a phenyl group, a naphthyl group, a biphenyl group and the like, with preference given to a phenyl group.
  • heterocyclic residue a 5- to 8-membered aromatic heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, a bicyclic or tricyclic heterocyclic group condensed therewith and the like can be mentioned.
  • Examples thereof include pyrrolyl group (1-, 2- or 3-pyrrolyl group), furyl group (2- or 3-furyl group), thienyl group (2- or 3-thienyl group), imidazolyl group (1-, 2-, 4- or 5-imidazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), isoxazolyl group (3-, 4- or 5-isoxazolyl group), isothiazolyl group (3-, 4- or 5-isothiazolyl group), oxadiazolyl group (1,2,4-oxadiazol-3 or 5-yl group, 1,3,4-oxadiazol-2-yl group, 1,2,5-oxadiazol-3-yl group), thiadiazolyl group (1,2,4-thiadiazol-3 or 5-yl group, 1,3,4-thiadiazol-2-y
  • an optionally condensed 3- to 7-membered carbon ring such as C 6-10 arene (C 6-10 aryl) (e.g., benzene (phenyl), naphthalene (naphthyl) and the like), C 3-7 cycloalkane (cycloalkyl) (e.g., cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl) etc.), C 3-7 cycloalkene (C 3-7 cycloalkenyl group) (e.g., cyclopropene (cyclopronyl), cyclobutene (cyclobutenyl), cyclopentene (cyclopentenyl), cyclohexene (cyclohexeny
  • the substituent that the above-mentioned homocyclic ring may have, for example, (1) a C 1-6 allyl group optionally substituted by halogens (particularly, C 1-6 allyl group substituted by halogens is preferable), (2) a C 3-10 cycloalkyl group, (3) a C 2-10 alkenyl group, (4) a C 2-10 alkynyl group, (5) a C 6-10 aryl group, (6) a C 7-20 aralkyl group, (7) a nitro group, (8) a hydroxy group, (9) a mercapto group, (10) a oxo group, (11) a thioxo group, (12) a cyano group, (13) a carbamoyl group, (14) a carboxyl group, (15) a C 1-6 alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group etc.), (16) a sulfo, (17
  • Preferable examples of the “homocyclic ring optionally having a substituent” formed by R 3 and R 4 or R 4 and R 5 together with carbon atoms bonded thereto are C 3-7 cycloalkane and benzene, and more preferable examples are cyclopentane and cyclohexane.
  • heterocyclic ring a 5- to 8-membered heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, and a bicyclic or tricyclic heterocyclic group condensed therewith and the like can be mentioned.
  • heterocyclic ring examples include (1) a 5-membered heterocyclic ring containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, such as thiophene (thienyl group), furan (furyl group), pyrrole (pyrrolyl group), pyrroline (pyrrolinyl group), pyrrolidine (pyrrolidinyl group), 1,3-dioxole (1,3-dioxolyl group), oxazole (oxazolyl group), thiazole (thiazolyl group), pyrazole (pyrazolyl group), imidazole (imidazolyl group), imidazoline (imidazolinyl group), isoxazole (isoxazolyl group), isothiazole (isothiazolyl group), furazan (furazanyl group), 1,2,3-thiadiazole (1,2,3-thiadiazolyl group), 1,
  • bicyclic or tricyclic condensed heterocyclic ring a bicyclic or tricyclic condensed heterocyclic ring containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, such as benzofuran (benzofuryl group), benzothiazole (benzothiazolyl group), benzoxazole (benzoxazolyl group), tetrazolo[1,5-b]pyridazine (tetrazolo[1,5-b]pyridazinyl group), triazolo[4,5-b]pyridazine (triazolo[4,5-b]pyridazinyl group), benzimidazole (benzimidazolyl group), quinoline (quinolyl group), isoquinoline (isoquinolyl group), cinnoline (cinnolinyl group), phthalazine (phthalazinyl group), quinazoline (quinazolin
  • the above-mentioned heterocyclic ring may have, for example, (1) a C 1-6 allyl group, (2) a C 2-6 alkenyl group, (3) a C 2-6 alkynyl group, (4) a C 3-6 cycloalkyl group, (5) a cycloalkenyl group, (6) a C 7-11 aralkyl group, (7) a C 6-14 aryl group, (8) a C 1-6 alkoxy group, (9) a C 6-14 aryloxy group (e.g., phenoxy group etc.), (10) a C 1-6 alkanoyl group (e.g., formyl group, acetyl group, propionyl group, n-butyryl group, iso-butyryl group etc.), (11) a C 6-14 arylcarbonyl group (e.g., benzoyl group etc.), (12) a C 1-6 alkanoyloxy group (e.g., formy
  • heterocyclic ring optionally having a substituent” formed by R 3 and R 4 or R 4 and R 5 together with carbon atoms bonded thereto are thiophene, furan, pyrrole, pyrroline, oxazole, thiazole, pyrazole, imidazole, imidazoline, isoxazole, isothiazole, furazan, 1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, 1,2,3-triazine, 1,2,4-triazine, 1,2,3-triazolidine, 2,2-difluoro-1,3-dioxole and 2,2,3,3-tetrafluoro-1,4-dioxane.
  • the substituent of the “homocyclic ring optionally having substituents” and the substituent of the “heterocyclic ring optionally having substituents” are preferably selected from the group consisting of (1) C 1-6 alkyl group optionally substituted by halogen atoms, (2) nitro group, (3) hydroxy group, (4) mercapto group, (5) cyano group, (6) carbamoyl group, (7) carboxyl group, (8) C 1-6 alkoxycarbonyl group, (9) sulfo group, (10) halogen atom, (11) C 1-6 alkoxy group, (12) C 1-6 alkylthio group, (13) C 1-6 alkylsulfinyl group, (14) C 1-6 alkylsulfonyl group, (15) amino group, (16) mono- or di-C 1-4 allylamino group, (17) C 1-6 alkanoyl group and (18) C 1-6 alkanoyloxy group.
  • the “pharmaceutically acceptable salt” may be any as long as it forms a nontoxic salt with the aforementioned compound represented by the formula (1).
  • examples thereof include, but are not limited to, salts with various inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate and the like; salts with organic acids such as formate, acetate, trifluoroacetate, propionate, oxalate, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate, adipate, tartrate, malate, citrate, benzoate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate and the like; sulfonates such as methanesulfonate, ethanesulfonate, isethionate, benzenesul
  • the above-mentioned compound represented by the formula (1) may have various isomers.
  • E form and Z form are present as geometric isomers, and when an asymmetric carbon atom exists, enantiomer and diastereomer as stereoisomers based thereon exist, and a tautomer can exist. Accordingly, the present invention encompasses all of these isomers and mixtures thereof.
  • the compound of the present invention encompasses prodrug compounds and metabolites.
  • prodrug compound a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group and which, after administration to the body, restores to the original compound to show its inherent efficacy, including a complex and a salt free of covalent bond.
  • a compound wherein the carboxyl group of the compound represented by the formula (1) is modified by ethyl group, pivaloyloxymethyl group, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, phenyl group, o-tolyl group and the like; a compound wherein the hydroxyl group of the compound represented by the formula (1) is modified by acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group or sulfo group; a compound wherein the amino group of the compound represented by the formula (1) is modified by he
  • R 1 is preferably a C 1-6 allyl group optionally substituted by halogen atoms, more preferably a trifluoromethyl group.
  • R 2 is preferably a halogen atom, a C 1-6 alkyl group optionally substituted by halogen atoms or a cyano group, more preferably a trifluoromethyl group or a cyano group.
  • R 3 and R 4 are each preferably a hydrogen atoms, a halogen atom, a C 1-6 allyl group optionally substituted by halogen atoms, a C 1-6 alkoxy group optionally substituted by halogen atoms, a C 1-6 allylthio group optionally substituted by halogen atoms or R 3 and R 4 form a homocyclic ring together with carbon atoms bonded thereto.
  • R 5 is preferably a hydrogen atom.
  • R 6 is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a hydrogen atom, a methyl group or an ethyl group.
  • n is preferably 0, 1 or 2.
  • Ring B and (R 6 ) n are each preferably
  • R 60 , R 61 and R 62 are as defined above, more preferably
  • R 60 and R 61 are as defined above.
  • A is preferably —N(R 7 )(R 8 ), more preferably that wherein R 7 is a C 1-6 alkyl group and R 8 is a C 4-10 cycloalkylalkyl group optionally substituted by —(CH 2 ) r —COOR 10 (wherein r and R 10 are as defined above) or a C 1-6 alkyl group substituted by carboxyl group.
  • the compound of the present invention, a prodrug thereof and a pharmaceutically acceptable salt thereof have superior CETP inhibitory activity in mammals (e.g., human, monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like), and can be used as CETP activity inhibitors.
  • mammals e.g., human, monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like.
  • a prodrug thereof and a pharmaceutically acceptable salt thereof are useful as pharmaceutical agents effective for the prophylaxis or treatment of the diseases in which CETP is involved (e.g., hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, heart ischemia, thrombosis, cardiac infarction, reperfusion injury, angioplasty restenosis, hypertension, diabetic vascular complications, obesity or endotoxemia etc.), particularly as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases.
  • diseases in which CETP e.g., hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial
  • a prodrug thereof or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with a pharmacologically acceptable carrier, excipient, diluent, filler, disintegrant, stabilizer, preservative, buffer, emulsifier, aromatic, coloring agent, sweetening agent, thickening agent, corrigent, dissolution aids, and other additives, which are known per se, specifically water, vegetable oil, alcohol such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydrates such as lactose, starch and the like, magnesium stearate, talc, lanolin, petrolatum and the like, and can be administered orally or parenterally in the form of tablet, pill, powder, granule, suppository, injection, eye drop, liquid, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like.
  • a pharmacologically acceptable carrier excipient
  • the dose of the pharmaceutical agent of the present invention varies depending on the kind and severity of the disease, the compound to be administered and administration route, age, sex and body weight of patients and the like, it is generally about 1-1000 mg, particularly about 50 mg-800 mg in the amount of the compound represented by the formula (1) of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof per day for an adult by oral administration.
  • the pharmaceutical agent of the present invention may be administered alone or concurrently with a different prophylactic or therapeutic agent for hyperlipidemia and/or a prophylactic or therapeutic agent for arteriosclerotic diseases, or may be used concurrently with a different pharmaceutical agent (e.g., therapeutic agent for obesity, therapeutic agent for diabetes, therapeutic agent for hypertension, therapeutic agent for arteriosclerosis, therapeutic agent for coronary artery disease etc.).
  • a different pharmaceutical agent e.g., therapeutic agent for obesity, therapeutic agent for diabetes, therapeutic agent for hypertension, therapeutic agent for arteriosclerosis, therapeutic agent for coronary artery disease etc.
  • a different therapeutic agent for hyperlipidemia is expected to provide an extremely superior synergistic effect of particularly remarkable suppression of blood cholesterol.
  • current use means a combined use of the compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof with a different pharmaceutical agent, such as a therapeutic agent for hyperlipidemia, wherein the mode of use thereof is not particularly limited.
  • a pharmaceutical composition containing the compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof and a different pharmaceutical agent includes both the administration of a pharmaceutical composition containing the compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof and a different pharmaceutical agent, and the simultaneous or staggered administration of respective preparations produced separately without mixing.
  • the dose of the different pharmaceutical agent to be used concurrently varies depending on the kind and severity of the disease, administration route, age, sex and body weight of patients and the like, it is generally about 1-1000 mg, particularly about 50 mg-800 mg thereof per day for an adult by oral administration.
  • statin pharmaceutical agents such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and the like can be mentioned.
  • mazindol As a therapeutic agent for obesity to be used concurrently with the pharmaceutical agent of the present invention, mazindol and the like can be mentioned.
  • insulin preparations e.g., glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide etc.
  • insulin secretagogues e.g., nateglinide etc.
  • sulfonamides e.g., glybuzole etc.
  • biguanides e.g., metformin hydrochloride, buformin hydrochloride etc.
  • ⁇ glucosidase inhibitors e.g., voglibose, acarbose etc.
  • insulin sensitizers e.g., pioglitazone hydrochloride etc.
  • loop diuretics e.g., furosemide sustained-release preparation etc.
  • angiotensin converting enzyme inhibitors e.g., captopril, captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine etc.), angiotensin II receptor antagonists (e.g., losartan potassium, candesartan cilexetil etc.), Ca antagonists (e.g., nicardipine hydrochloride, nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine,
  • the pharmaceutical agent of the present invention can be administered not only to humans but also to other mammals (e.g., monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like).
  • mammals e.g., monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like.
  • reaction in each step may be carried out according to a conventional method, wherein isolation and purification are performed by appropriately selecting or combining conventional methods, such as crystallization, recrystallization, column chromatography, preparative HPLC and the like.
  • the production method of the compound represented by the formula (1) is exemplarily shown in the following.
  • This step is directed to a general reductive amination.
  • the compound represented by the formula (2) is reacted with a compound represented by the formula (3) in the presence of a reducing agent in a solvent to give a compound represented by the formula (4).
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as acetic acid, N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination.
  • Preferable solvents in this reaction are chloroform and dichloromethane.
  • sodium triacetoxyborohydride sodium cyanoborohydride, sodium borohydride and the like can be mentioned.
  • a preferable reducing agent in this reaction is sodium triacetoxyborohydride.
  • This step is directed to a general alkylation.
  • a compound represented by the formula (4) is reacted with a compound represented by the formula (5) in a solvent in the presence of a base to give one of the object compounds, which is represented by the formula (1-a).
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is N,N-dimethylformamide.
  • alkali metal hydrides e.g., sodium hydride, potassium hydride etc.
  • alkali metal alkoxides e.g., sodium ethoxide, sodium methoxide, potassium tert-butoxide etc.
  • alkyllithiums e.g., n-butyllithium, sec-butyllithium etc.
  • alkali metal amides e.g., lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide etc.
  • alkali metal carbonates e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.
  • alkali metal hydroxides e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide etc.
  • alkali metal phosphates e.g., sodium phosphate, potassium phosphate etc.
  • organic bases e.g., triethylamine, pyridine, N-methylmorpholine etc.
  • the obtained object compound may be subjected to a salt-forming reaction to give a desired salt.
  • This step is directed to a general reductive amination.
  • a compound represented by the formula (6) is reacted with a compound represented by the formula (3) in a solvent in the presence of a reducing agent to give a compound represented by the formula (7).
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination.
  • Preferable solvents in this reaction are dichloromethane and toluene.
  • sodium triacetoxyborohydride sodium cyanoborohydride, sodium borohydride, lithium hydride, aluminum hydride and the like can be mentioned.
  • a preferable reducing agent in this reaction is sodium borohydride.
  • the formula (6) is reacted with the formula (3) to once give a Schiff base, which is followed by a reduction.
  • azeotropic dehydration may be conducted in a solvent such as benzene, toluene, ethanol and the like without catalyst or in the presence of an acid catalyst such as hydrochloric acid, acetic acid and the like, or a method using a dehydrating agent such as molecular sieves and the like in an aprotic solvent such as methylene chloride, toluene and the like may be employed.
  • a compound represented by the formula (8) which is obtained by treating the formula (2) by a general reduction, is reacted with thionyl chloride in a solvent such as toluene, tetrahydrofuran, chloroform and the like to give a compound wherein hydroxyl group of the formula (8) is chlorinated.
  • a similar reaction as in Step 1-2 using the obtained compound and a compound represented by the formula (7) gives one of the object compounds, which is represented by the formula (1-a).
  • This step is directed to a general reductive amination.
  • a compound represented by the formula (2) is reacted with a compound represented by the formula (9) in a solvent in the presence of a reducing agent to give a compound represented by the formula (10).
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is dichloromethane.
  • sodium triacetoxyborohydride sodium cyanoborohydride, sodium borohydride and the like can be mentioned.
  • a preferable reducing agent in this reaction is sodium triacetoxyborohydride.
  • Step 1-2 This step is directed to a general nucleophilic substitution reaction.
  • a compound represented by the formula (10) is reacted with a compound represented by the formula (11) to give one of the object compounds, which is represented by the formula (1-a).
  • a compound represented by the formula (10) is reacted with compound (12) in a solvent.
  • the obtained residue is reacted with hydrazine hydrate in a solvent in the presence of an acid to give a compound represented by the formula (1-b), which is one of the object compounds.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like
  • hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like
  • halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like
  • ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like
  • polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is dichloromethane.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is 1,2-dimethoxyethane.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and the like
  • organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like
  • a mixture thereof can be mentioned, with preference given to methanesulfonic acid.
  • a compound represented by the formula (10) is reacted with cyanogen bromide in a solvent in the presence of a base, and the obtained residue is reacted with hydroxylamine in a solvent.
  • the obtained residue is reacted with an acylating agent, such as acid chloride represented by the formula (13) and the like, in a solvent to give a compound represented by the formula (1-c), which is one of the object compounds.
  • solvent to be used for the first reaction for example, alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is methanol.
  • alkali metal carbonates e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.
  • alkali metal phosphates e.g., sodium phosphate, potassium phosphate etc.
  • organic bases e.g., triethylamine, pyridine, N-methylmorpholine etc.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like
  • hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like
  • halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like
  • alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like
  • polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is dioxane.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination.
  • a preferable solvent in this reaction is pyridine.
  • A, B and R 1 to R 6 may be further subjected to conversion of a functional group according to a known method, after synthesis of compound (I) in the above-mentioned production method.
  • a functional group conversion reaction for example, when the terminal of substituent A is an ester, the obtained compound (1-a) is subjected to a conventional ester hydrolysis, whereby a compound having a carboxyl group as the terminal of substituent A can be easily obtained.
  • the solvent to be used for this ester hydrolysis reaction for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like, and water can be mentioned, which may be used alone or in combination.
  • metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and the like can be mentioned.
  • a compound represented by the formula (2) which is a starting material of the above-mentioned production method, can be produced according to a conventionally known method. In the following, some examples thereof are explained.
  • R 3 , R 4 , R 5 and R 7 are as defined above, and —CH 2 R 8a is a group corresponding to the aforementioned R 8 .
  • Aniline represented by the formula (15) is reacted with an acid halide and the like in the presence or absence of a base under cooling to heating in an organic solvent, water, or without solvent, whereby a compound represented by the formula (16) can be synthesized (Step 4-1).
  • the compound represented by the formula (16) is reacted with a reducing agent such as lithium aluminum hydride, Red-Al, sodium borohydride and the like under cooling to heating in an organic solvent, whereby a compound represented by the formula (17) can be synthesized (Step 4-2).
  • the compound represented by the formula (17) is reacted with allyl halide and the like in the presence or absence of a base under cooling to heating in an organic solvent or water, or without solvent, whereby a compound represented by the formula (18) can be synthesized (Step 4-3).
  • the compound represented by the formula (18) is reacted using a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-a), which is one of the desired starting materials, can be synthesized (Step 4-4).
  • R 3 , R 4 , R 5 , R 11 , R 12 and R 13 are as defined above.
  • Phenol represented by the formula (19) is reacted with alcohol represented by the formula; (R 11 )(R 12 )(R 3 )COH (wherein R 11 , R 12 and R 13 are as defined above) in the presence of triphenylphosphine using a condensing agent such as diethyl azodicarboxylate and the like under cooling to heating in an organic solvent or water, or without solvent, whereby a compound represented by the formula (20) can be synthesized (Step 5-1).
  • a condensing agent such as diethyl azodicarboxylate and the like
  • the compound represented by the formula (20) is reacted using a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-b), which is one of the desired starting materials, can be synthesized (Step 5-2).
  • R 3 , R 4 , R 5 , R 11 and R 12 are as defined above, and X is a halogen atom.
  • Halobenzene represented by the formula (21) and butyllithium are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with ketone, aldehyde and the like, whereby a compound represented by the formula (22) can be synthesized (Step 6-1).
  • the compound represented by the formula (22) is hydrogenated in the presence of a catalyst such as palladium hydroxide and the like at room temperature or under heating in an organic solvent or water, whereby a compound represented by the formula (23) can be synthesized (Step 6-2).
  • the compound represented by the formula (23) is reacted using a brominating agent such as bromosuccinimide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (24) can be synthesized (Step 6-3).
  • a brominating agent such as bromosuccinimide and the like under cooling to heating in an organic solvent or without solvent
  • a compound represented by the formula (24) can be synthesized (Step 6-3).
  • the compound represented by the formula (24) and butyllithium are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with N,N-dimethylformamide and the like, whereby a compound represented by the formula (2-c), which is one of the desired starting materials, can be synthesized (Step 6-4).
  • R 3 , R 4 , R 5 , R 7 and R 8 are as defined above.
  • a fluorobenzene compound represented by the formula (25) and LDA, butyllithium and the like are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with N,N-dimethylformamide and the like, whereby a compound represented by the formula (26) can be synthesized (Step 7-1).
  • the compound represented by the formula (26) is reacted with an amine represented by the formula; (R 7 )(R 8 )NH in the presence of a base such as potassium carbonate and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-d), which is one of the desired starting materials, can be synthesized (Step 7-2).
  • Example 6b In a similar manner as in Example 4, the title compound (50 mg) was obtained from N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine (68 mg) obtained in Example 6b) (see Table 2).
  • hexane solution was added dropwise over 1.5 hr to a mixture of tetrahydrofuran (300 ml) and 1.0 M solution (600 ml) of s-butyllithium in hexane, which had been cooled to ⁇ 78° C. and stirred. The stirring was continued for 1 hr and N,N-dimethylformamide (57 ml) was added dropwise. After completion of the dropwise addition, 2N aqueous hydrochloric acid (600 ml) was added and the mixture was allowed to warm to room temperature. This was extracted with hexane and washed with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated to give the title compound (61.54 g, 52%).
  • the compounds shown in Table 35 can be produced in a similar manner.
  • the mixture was subjected to density gradient centrifugation (227,000 ⁇ g, 4° C., 17 hr) and a fraction showing a specific density of d>1.125 g/mL (HDL 3 fraction) was harvested.
  • the obtained fraction was dialyzed against PBS solution [10 mmol/L Na 2 HPO 4 ; 10 mmol/L NaH 2 PO 4 ; 0.15 mol/L NaCl; 1 mol/L EDTA (pH 7.4)].
  • tritium-labeled cholesterol 37 MBq was dissolved in 95% ethanol, gradually added to the above-mentioned HDL 3 fraction with stirring and incubated at 37° C. for 18 hr.
  • tritium-labeled cholesterol was esterified by the action of lecithin acyl transferase (LCAT) present on the HDL 3 surface and taken up into HDL 3 as tritium-labeled cholesteryl ester ([ 3 H]CE)].
  • LCAT lecithin acyl transferase
  • the donor lipoprotein obtained above was added to plasma of healthy subject to prepare a [ 3 H]CE-HDL 3 -containing plasma (1,000 dpm/ ⁇ L).
  • the compound was dissolved in dimethyl formamide.
  • a solution of the compound or a solvent alone (2 ⁇ L) and the [ 3 H]CE-HDL 3 -containing plasma (100 ⁇ L) were added into a microtube, and this was incubated at 37° C. or 4° C. for 4 hr. After ice-cooling, TBS solution [100 ⁇ L, 20 mmol/L Tris; 0.15 mol/L NaCl (pH 7.4)] containing 1 mol/L magnesium chloride and 2% dextran sulfate was added to each microtube and the mixture was thoroughly stirred.
  • the mixture was centrifuged (10,000 ⁇ g, 4° C., 10 min), and the radioactivity in the obtained supernatant (HDL fraction) was measured with a scintillation counter.
  • the difference in the measurement values obtained by incubation of solvent alone at 4° C. and 37° C. was taken as CETP activity, and the proportion of decrease in the difference in the measurement values of specimen was taken as percent inhibition of CETP activity.
  • the concentration of the compound necessary for inhibiting the CETP activity by 50% was calculated as an IC 50 value. The results are shown in the following.
  • Example No. IC 50 ( ⁇ M) Example No. IC 50 ( ⁇ M) 1 0.23 2 0.08 3 0.24 4 0.18 7 0.27 8 0.63 10 0.23 11 0.63 12 0.25 13 0.58 26 0.47 27 0.58 28 0.44 33 0.56 34 0.22 35 0.35 36 0.34 37 0.80 38 0.47 39 0.88 40 0.39 41 0.51 42 0.70 43 0.55 44 0.36 45 0.49 46 0.39 51 0.41 52 0.37 53 0.70 54 0.79 55 0.77 58 0.715 59 0.43 60 0.78 63 0.64 64 0.75 65 0.29 66 0.87 67 0.26 68 0.28 69 0.34 70 0.54 71 0.44 72 0.39 73 0.19 74 0.40 75 0.41
  • the IC 50 values in Table show average values.
  • Example No. IC 50 ( ⁇ M) Example No. IC 50 ( ⁇ M) 76 0.29 77 0.54 78 0.32 79 0.89 80 0.43 81 0.33 82 0.59 86 0.941 89 0.69 91 0.56 92 0.19 93 0.76 96 0.31 98 0.30 99 0.53 102 0.59 103 0.43 104 0.35 105 0.60 107 0.56 108 0.25 109 0.16 111 0.19 114 0.28 115 0.09 118 0.09 119 0.13 120 0.28 121 0.23 122 0.24 127 0.37 129 0.61 131 0.17 135 0.22 137 0.14 138 0.16 140 0.12 141 0.12 142 0.06 143 0.10
  • the IC 50 values in Table show average values.
  • the compound of the present invention was suspended in 0.5% methyl cellulose solution and orally administered once to a healthy hamster with a plastic gavage needle. Blood was taken at 2 or 4 hr after the administration and CETP activity in plasma was measured according to the following method.
  • the donor lipoprotein obtained above was added to hamster plasma (100 ⁇ L) to prepare [ 3 H]CE-HDL 3 -containing plasma (ca. 1,000 dpm/ ⁇ L).
  • the [ 3 H]CE-HDL 3 -containing plasma was dispensed to two microtubes by 25 ⁇ L each, and one was incubated at 37° C. and the other was incubated at 4° C. for 4 hr each. After ice-cooling, TBS solution (50 ⁇ l) containing 1 mol/L magnesium chloride and 2% dextran sulfate was added to each microtube and the mixture was thoroughly stirred. After keeping at 41° C.
  • the CETP activity inhibitory ratio of each compound administration group based on the CETP activity of the solvent administration group as 100% was calculated from the following formula and expressed in %.
  • CETP activity inhibitory ratio (%) 100 ⁇ [(CETP activity of each compound administration group)/(CETP activity of solvent administration group) ⁇ 100]
  • HDL cholesterol increase ratio(%) [(HDL cholesterol content of each compound administration group/HDL cholesterol content of solvent administration group) ⁇ 100] ⁇ 100
  • HDL cholesterol increase content (%) compound Dose (mg/kg) 4 (hr later) 8 (hr later) 115 3 23.3 30.7 118 3 21.1 31.7 142 3 20.3 31.9 143 3 17.0 21.3 154 3 13.3 22.4 157 3 17.9 27.1 158 3 14.8 23.7
  • the HDL cholesterol increase ratios in Table show average values.
  • Foods were prepared (manufactured by Oriental Bio-Service Co.) by adding simvastatin (0.002%), compound (0.2%) of Example 168, or simvastatin (0.002%)+compound (0.2%) of Example 168 to a high cholesterol food, and each food was given to the grouped animals by 100 g/day per rabbit for 15 days.
  • the total blood was taken from the carotid artery under anesthesia, HDL cholesterol content, total cholesterol content and ApoA-I content in plasma were measured.
  • the arteriosclerosis index was calculated from [(total cholesterol content-HDL cholesterol content)/HDL cholesterol content].
  • the HDL 3 fraction was separated from plasma by ultracentrifugation and the cholesterol content of the fraction was measured.
  • arteriosclerotic index, ApoA-1 content and HDL 3 cholesterol content are shown based on the value of the control group as 100%.
  • the compound and a salt thereof of the present invention have superior CETP activity inhibitory effect. Therefore, they can decrease IDL, VLDL and LDL that promote arteriosclerosis and increase HDL that acts suppressively. As a result, they are useful as prophylactic or therapeutic agents for hyperlipidemia. In addition, they are useful as prophylactic or therapeutic agents for arteriosclerotic disease and the like.
  • the compound of the present invention can be used concurrently with a different pharmaceutical agent, particularly other therapeutic agents for hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension.

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Abstract

A dibenzylamine compound represented by the formula (1)
Figure US07807701-20101005-C00001
wherein R1 and R2 are each a C1-6 allyl group optionally substituted by halogen atoms and the like; R3, R4 and R5 are each a hydrogen atom, a halogen atom and the like, or R3 and R4 may form, together with carbon atoms bonded thereto, a homocyclic or heterocyclic ring optionally having substituent(s); A is —N(R7)(R8) and the like; ring B is an aryl group or a heterocyclic residue; R6 is a hydrogen atom, a halogen atom, a nitro group, a C1-6 allyl group and the like; n is an integer of 1 to 3, a prodrug thereof and a pharmaceutically acceptable salt thereof show selective and potent CETP inhibitory activity, and therefore, they can be provided as therapeutic or prophylactic agents for hyperlipidemia or arteriosclerosis and the like.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application is a continuation of copending U.S. patent application Ser. No. 10/503,185, filed Oct. 12, 2004, which is the national phase of International Patent Application No. PCT/JP03/11041, filed Aug. 29, 2003, which claims priority to Japanese Patent Application Nos. 107161/2003, filed Apr. 10, 2003 and 255604/2002, filed Aug. 30, 2002, all of which are incorporated by reference.
TECHNICAL FIELD
The present invention relates to a novel CETP activity inhibitor, particularly a therapeutic agent or a prophylactic agent of arteriosclerosis or hyperlipidemia.
BACKGROUND ART
Regarding the relationship between arteriosclerotic diseases and serum lipoprotein, it has been considered for some time that a certain relationship exists from the results of many epidemiological researches. For example, Badimon et al. (J. Clin. Invest., 85, 1234-1241 (1990)) reported that intravenous injection of fractions containing HDL (high density lipoprotein) and VHDL (very high density lipoprotein) to cholesterol-loaded rabbits resulted in the observation of not only prevention of progression of arteriosclerotic lesion but also regression thereof, and HDL and VHDL are considered to have an anti-arteriosclerotic action in the relationship between arteriosclerotic diseases and serum lipoprotein.
In recent years, the presence of a protein that transfers lipid between blood lipoproteins, or CETP (cholesteryl ester transfer protein), has been clarified. The presence of CETP was first pointed out in 1965 by Nichols & Smith (J. Lipid Res., 6, 206, 1965), and thereafter its cDNA was cloned in 1987 by Drayna et al. The molecular weight thereof is 74,000 Da as glycoprotein and about 58,000 Da when sugar chain is completely cleaved. Its cDNA consists of 1656 residues and encodes 476 amino acids following 17 signal peptides. Since about 44% thereof consists of hydrophobic amino acids, it has extremely high hydrophobicity and is easily inactivated by oxidation. In addition, it has been confirmed that CETP is produced in the organs such as liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle, heart muscle and the like, and produced in cells of the cell types of human monocyte-derived macrophage, B lymphocyte, fat cell, small intestinal epithelial cell, CaCo2 cell, hepatocyte (exemplified by human liver cancer cell-derived cell line, HepG2 cells) and the like. Besides the above-mentioned tissues, it is present in cerebrospinal fluid and semen, and its presence has been confirmed in culture media of human neuroblastoma and neuroglioma cells, choroid plexus of sheep and the like.
It has been also clarified that CETP is involved in the metabolism of any lipoprotein in living organisms, and has a major role in the reverse cholesterol transfer system. Namely, CETP has drawn attention as a mechanism for preventing accumulation of cholesterol in peripheral cells and preventing arteriosclerosis. In fact, with regard to HDL having an important role in this reverse cholesterol transfer system, a number of epidemiological researches have shown that a decrease in CE (cholesteryl ester) of HDL in blood is one of the risk factors of coronary artery diseases. It has been also clarified that the CETP activity varies depending on the animal species, wherein arteriosclerosis due to cholesterol-loading is hardly induced in animals with lower activity, and in reverse, easily induced in animals with higher activity, and that hyper-HDL-emia and hypo-LDL (low density lipoprotein)-emia are induced in the case of CETP deficiency, thus rendering the development of arteriosclerosis difficult, which in turn led to the recognition of the significance of blood HDL, as well as significance of CETP that mediates transfer of CE in HDL into blood LDL.
Free cholesterol (FC) synthesized in and secreted from the liver is taken up by very low density lipoprotein (VLDL). Then, due to the action of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), VLDL is metabolized in blood into LDL via intermediate density lipoprotein (IDL). LDL is taken up by peripheral cells via an LDL receptor and FC is supplied to the cells. Conversely from such flow from the liver to the peripheral cells, there exists a flow of cholesterol from peripheral cells toward the liver, which is called a reverse cholesterol transfer system. In other words, FC accumulated in the peripheral tissues is drawn by HDL, further esterified on HDL by the action of LCAT (lecithin-cholesterol acyltransferase) to form CE, and transferred to the hydrophobic core part of HDL, whereby HDL matures into spheric HDL particles. CE in HDL is transferred by CETP present in blood to apoB-containing lipoproteins such as VLDL, IDL, LDL and the like, and in return, TG is transferred to HDL at a molar ratio of 1:1. CE transferred to apoB-containing lipoprotein is taken up by the liver via LDL receptor in the liver, thereby indirectly transferring cholesterol to the liver. Moreover, there is a mechanism in which HDL takes up apoprotein E secreted from macrophage and the like to become apoprotein E-containing HDL rich in CE, and then is directly taken up by the liver via LDL receptor or remnant receptor. There also exists a path in which HDL particles are not taken up by the liver and only CE in HDL is selectively taken up by hepatocytes. Furthermore, another path exists in which HDL particles are taken up by hepatocytes via what is called an HDL receptor in the liver.
Namely, in the state of enhanced CETP activity, since CE transfer from HDL increases, CE in HDL decreases, and CE in VLDL, IDL and LDL increases. When take up of IDL and LDL by the liver increases, down-regulation is imposed on the LDL receptor, and LDL in blood increases. In contrast, in the CETP deficient state, HDL draws cholesterol from peripheral cells with the aid of LCAT, gradually increases its size and acquires apo E. Then, apo E-rich HDL is taken up by the liver via LDL receptor in the liver and catabolized. However, since this mechanism does not function sufficiently in human, large HDL dwells in the blood. Consequently, cholesterol pool in the liver becomes smaller and up-regulation is imposed on the LDL receptor, thereby decreasing LDL. Accordingly, selective inhibition of CETP can lower IDL, VLDL and LDL that promote arteriosclerosis and increase HDL that acts suppressively thereon, and produces expectation for the provision of an unprecedented prophylactic or therapeutic agent for arteriosclerosis or hyperlipidemia.
While many attempts have been made in recent years to develop a drug that inhibits such activity of CETP, a compound having a satisfactory activity has not been developed yet.
Meanwhile, many reports have been found recently on the compounds aiming at inhibiting such activity of CETP. For example, Biochemical and Biophysical Research Communications 223, 42-47 (1996) discloses dithiodipyridine derivatives, substituted dithiodibenzene derivatives and the like as compounds that inactivate CETP by modifying cysteine residue. However, this reference does not contain any description of the compound of the present invention, not to mention a description suggestive thereof.
In addition, WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETP activity inhibitors. However, this publication does not contain any description suggesting the compound of the present invention.
Moreover, JP-B-45-11132, JP-B-45-2892, JP-B-45-2891, JP-B-45-2731 and JP-B-45-2730 disclose mercaptoanilides substituted by higher fatty acid such as o-isostearoylaminothiophenol and the like, as a compound having an action to prevent arteriosclerosis. However, these publications only mention the presence of an effect to prevent arteriosclerosis and lack description of Experimental Example that support the effect, much less a description of inhibition of CETP activity. Moreover, no description is found that suggests the compound of the present invention.
JP-T-2001-512416 (WO98/04528) discloses a biaryl compound that inhibits CETP. However, this publication has no description that suggests the compound of the present invention.
WO00/17164, WO00/17166 and WO01/40190 disclose 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline as a CETP inhibitor. However, these publications contain no description that suggests the compound of the present invention.
On the other hand, various compounds having a structure like the compound of the present invention have been reported. For example, JP-A-2001-106666 and WO01/10825 disclose carbamate derivatives characterized in that phenyl group has an oxime ether group. However, the compounds of these publications are compounds useful as antimicrobial agents for agriculture or gardening, and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO00/69810 discloses compounds such as 3-(4-{[N-[3-(2,6-dichlorophenyl)acryloyl]-N-(4-tert-butylbenzyl)amino]methyl}benzoylamino)propionic acid and the like. However, the compound of this publication is useful as a glucagon antagonist, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/67204 discloses compounds such as 1-[N-(4-chlorobenzyl)-N—(N,N-dimethylcarbamoyl)aminomethyl]-4-guanidinomethylbenzene and the like. However, the compound of this publication is useful as an analgesic, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/44987 and U.S. Pat. No. 6,218,426 disclose compounds such as N-(4-tert-butylbenzyl)-N-[4-(guanidinomethyl)benzyl]benzamide and the like useful as a gonadotropin-releasing hormone antagonist/agonist. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 5,834,514 and JP-T-9-512556 (WO95/29672) disclose that halomethylamide compounds such as N-benzyl-N-(2,4-dichlorobenzyl)chloroacetamide and the like are useful as IL-1β protease activity inhibitors. However, these publications lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO97/24328 discloses 2-amino-heterocyclic compounds such as N,N-bis(2,4-dimethoxybenzyl)-N′-(4-methoxyphenyl)urea and the like. However, the compound of this publication is useful as a leukotriene synthesis inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO96/10559 discloses urea derivatives such as 1-benzyl-1-[3-(pyrazol-3-yl)benzyl]-3-(2,4,6-trimethylphenyl)urea and the like. However, the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,623,662 discloses that urea compounds such as 1-benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea and the like are useful as acyl-CoA:cholesterol acyltransferase inhibitors. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,473,579 discloses urea compounds such as 1,1-dibenzyl-3-(2,4-dimethylphenyl)-3-phenylurea and the like. However, the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,122,255, U.S. Pat. No. 4,064,125, U.S. Pat. No. 4,151,354 and U.S. Pat. No. 4,127,606 disclose compounds such as N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]-3-phenyl-N-(phenylmethyl)-2-propenamide and the like. However, the compounds of these publications are useful as antiinflammatory agents and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/18066 discloses amide carboxylic acid compounds such as ethyl 2-butyl-3-[4-[2-[N-benzyl-(4-pyridin-2-yl)amino]ethoxy]phenyl]propionate and the like having useful lipid-lowering action and the like. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof. Moreover, this publication lacks a disclosure of a structure such as the compound of the present invention, or even a description suggestive thereof.
In contrast, WO00/18724 discloses a compound having a structure similar to that of the present invention and a CETP inhibitory activity. To be specific, the following formula is disclosed.
Figure US07807701-20101005-C00002
When R2 and R3 form a hetero ring or cycloalkenyl in combination, the compound is structurally similar to the present invention. However, this invention lacks a concrete disclosure (Example) of ring B as shown in the present invention. In addition, this invention is distinct from the present invention in that the invention always has R1 (haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkenyloxyallyl).
In other words, this invention does not disclose a concrete structure as the compound of the present invention, not to mention a description suggestive thereof.
DISCLOSURE OF THE INVENTION
The present invention aims at providing a novel compound that selectively inhibits the activity of CETP. The present invention also aims at providing a compound useful as a prophylactic or therapeutic agent of arteriosclerosis or hyperlipidemia, which increases HDL cholesterol and simultaneously decreases LDL cholesterol and triglyceride by selectively inhibiting the activity of CETP, and which is free of a CYP inhibitory effect.
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects and found that the compounds shown in the following [1] to [13] have an effect to selectively inhibit the activity of CETP (hereinafter to be referred to as a CETP inhibitory effect), and are useful pharmaceutical agents, particularly, prophylactic or therapeutic agents of arteriosclerosis or hyperlipidemia. Moreover, they have found that a structure such as the formula (1) provides a potent CETP inhibitory effect, which resulted in the completion of the present invention. More particularly, the following [1] to [76] are provided.
[1] A dibenzylamine compound represented by the formula (1)
Figure US07807701-20101005-C00003
wherein
  • R1 and R2
    • are the same or different and each is a halogen atom, a nitro group, a cyano group or a C1-6 alkyl group optionally substituted by halogen atoms;
  • R3, R4 and R5
    • are the same or different and each is a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted by halogen atoms, a C1-6 allylthio group optionally substituted by halogen atoms or a C1-6 alkoxy group optionally substituted by halogen atoms, or R3 and R4 or R4 and R5 may form, together with carbon atoms bonded thereto, a homocyclic ring optionally having substituent(s) or a heterocyclic ring optionally having substituent(s);
  • A is —N(R7)(R8) (wherein R7 and R8 are the same or different and each is a hydrogen atom, a C1-6 alkyl group (wherein C1-6 allyl group is optionally substituted by phenyl group or
    • —(CH2)m—COOR9 (wherein R9 is a hydrogen atom or a C1-6 allyl group and m is 0 or an integer of 1 to 5)) or a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group, C1-6 alkoxy group or phosphono group), —(CH2)q—CON(R20)(R21) (wherein R20 and R21 are the same or different and each is hydrogen atom or C1-6 allyl group and q is 0 or an integer of 1 to 5) or —(CH2)r—COOR10 (wherein R10 is hydrogen atom or C1-6 alkyl group and r is 0 or an integer of 1 to 5))), —C(R11)(R12)(R13) (wherein R11, R12 and R13 are the same or different and each is a hydrogen atom, a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by phenyl group or —COOR9 (wherein R9 is as defined above)) or a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 allyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group, C1-6 alkoxy group or phosphono group), —(CH2)q—CON(R20)(R21) (wherein R20, R21 and q are as defined above) or —(CH2)r—COOR10 (wherein R10 and r are as defined above))) or —O—C(R11)(R12)(R13) (wherein R11, R12 and R13 are as defined above);
  • ring B is an aryl group or a heterocyclic residue;
  • R6 is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C1-6 alkoxy group, a C2-6 alkenyl group or a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or —COOR14 (wherein R14 is a hydrogen atom or a C1-6 alkyl group)); and
  • n is an integer of 1 to 3
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [2] The dibenzylamine compound of the above-mentioned [1]
    wherein
  • R3, R4 and R5
    • are the same or different and each is a hydrogen atom, a halogen atom, a C1-6 allyl group optionally substituted by halogen atoms or a C1-6 alkoxy group optionally substituted by halogen atoms, or R3 and R4 or R4 and R5 may form, together with carbon atoms bonded thereto, a homocyclic ring optionally having substituent(s) or a heterocyclic ring optionally having substituent(s);
  • R7 and R8
    • are the same or different and each is a hydrogen atom, a C1-6 allyl group (wherein C1-6 alkyl group is optionally substituted by phenyl group or —COOR9 (wherein R9 is a hydrogen atom or a C1-6 allyl group)) or a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 alkyl group or —COOR10 (wherein R10 is a hydrogen atom or a C1-6 allyl group));
  • R11, R12 and R13
    • are the same or different and each is a hydrogen atom, a C1-6 allyl group (wherein C1-6 allyl group is optionally substituted by phenyl group or —COOR9 (wherein R9 is as defined above)) or a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 allyl group or —COOR10 (wherein R10 is as defined above));
  • R6 is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C1-6 alkoxy group or a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or —COOR14 (wherein R14 is a hydrogen atom or a C1-6 alkyl group)),
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [3] The dibenzylamine compound of the above-mentioned [1] or [2], wherein R1 is a C1-6 alkyl group substituted by halogen atoms, or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [4] The dibenzylamine compound of the above-mentioned [3], wherein R1 is a trifluoromethyl group, or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [5] The dibenzylamine compound of the above-mentioned [1], [3] or [4], wherein ring B and (R6)n are each
Figure US07807701-20101005-C00004
Figure US07807701-20101005-C00005
wherein R60, R61 and R62 are the same or different and each is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C1-6 alkoxy group, a C2-6 alkenyl group or a C1-6 allyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or
—COOR14 (wherein R14 is as defined above)) or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[6] The dibenzylamine compound of the above-mentioned [5], wherein ring B and (R6)n are each
Figure US07807701-20101005-C00006
wherein R60, R61 and R62 are as defined above or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[7] The dibenzylamine compound of the above-mentioned [6], wherein ring B and (R6)n are each
Figure US07807701-20101005-C00007
wherein R60 and R61 are as defined above or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[8] The dibenzylamine compound of any of the above-mentioned [1] and [3] to [7], wherein A is —N(R7)(R8) (wherein R7 and R8 are as defined in the above-mentioned [1]) or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[9] The dibenzylamine compound of the above-mentioned [8], wherein R7 is a C1-6 allyl group or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[10] The dibenzylamine compound of the above-mentioned [9], wherein R6 is a C1-6 allyl group or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[11] The dibenzylamine compound of the above-mentioned [1], which is selected from the group consisting of
  • N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine,
  • 3-{[N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrzol-5-yl)amine,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine hydrochloride,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine,
  • 5-{N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoic acid hydrochloride,
  • methyl trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine,
  • 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)amine hydrochloride,
  • 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrile hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)amine hydrochloride,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-3-ylamine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-2-ylamine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • 3-{[N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • methyl 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • methyl 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-ylmethyl)-N-ethylamino]pentanoate hydrochloride,
  • methyl 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • methyl trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • methyl trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • trans-4-{[N-(3-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,2,4]oxadiazol-3-yl)amine hydrochloride,
  • methyl trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • methyl trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate,
  • trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-[{N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • methyl 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methyl-isoxazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methyl-[1,2,4]thiadiazol-5-yl)amine,
  • 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • methyl 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • methyl 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]amino}tetrazol-2-yl)ethanol hydrochloride,
  • methyl 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • methyl 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • 5-[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-{N-[6-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}pentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-2,2-dimethylpentanoic acid hydrochloride,
  • 6-[N-(6-[([N′-3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methylindan-5-yl)-N-ethylamino]hexanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • (1-{2-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]ethyl}cyclopentyl)acetic acid hydrochloride,
  • trans-4-({N-[6-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}methyl)cyclohexanecarboxylic acid,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • (1-{2-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]ethyl}cyclopentyl)acetic acid,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-[{N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-({N-[3-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,
  • 1-{3-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]propyl}cyclohexanecarboxylic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]hexanoic acid hydrochloride,
  • trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylhexanoic acid hydrochloride,
  • 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylpentanoic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-5,5-dimethylhexanoic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-isobutylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid amide,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid methylamide,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid dimethylamide,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-chlorophenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(m-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-(3,5-dichlorobenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-ethyl-N-(2-{[N′-(2-methyl-2H-tetrazol-5-yl)-N′-(3-methyl-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-(3-chloro-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-ethyl-N-(2-{[N′-(2-methyl-2H-tetrazol-5-yl)-N′-(3-nitro-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-3-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)propionic acid hydrochloride,
  • trans-(4-{[N-(7-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-(4-{[N-(7-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-2-(4-{[N-(7-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetamide hydrochloride,
  • trans-N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[N′-ethyl-N′-(4-(methoxymethyl)cyclohexylmethyl)amino]-5-trifluoromethoxybenzyl}-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • trans-2-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)ethanol hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexylmethyl)phosphonic acid,
  • trans-4-{[N-(2-{[N′-(3-bromo-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-methoxyphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4,5-dimethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylthiophenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-4-({N-[2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-(2,2,2-trifluoroethyl)phenyl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-ethylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-isopropenylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid dihydrochloride,
  • trans-(4-[{N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonate,
  • ethyl trans-(4-{[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate and
  • trans-(4-[{N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [12] The dibenzylamine compound of the above-mentioned [1], which is selected from the group consisting of
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • trans-(4-[{N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid,
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid and
  • trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonate
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [13] The dibenzylamine compound of the above-mentioned [2], which is selected from the group consisting of
  • N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine,
  • 3-{[N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine hydrochloride,
  • N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine,
  • 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)amine hydrochloride,
  • 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrile hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)amine hydrochloride,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)amine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-3-ylamine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-2-ylamine hydrochloride,
  • N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride and
  • 3-{[N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride
    or a prodrug thereof or a pharmaceutically acceptable salt thereof.
    [14] A pharmaceutical composition comprising the dibenzylamine compound of any of the above-mentioned [1] to [1,3] or a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
    [15] A CETP activity inhibitor comprising a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
    [16] A therapeutic agent or a prophylactic agent for hyperlipidemia, which comprises a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
    [17] A method for treating or preventing hyperlipidemia, which comprises administering a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof to a mammal.
    [18] Use of a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof for the production of a therapeutic agent or a prophylactic agent for hyperlipidemia.
    [19] A therapeutic agent or a prophylactic agent for arteriosclerosis, which comprises a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
    [20] A method for treating or preventing arteriosclerosis, which comprises administering a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof to a mammal.
    [21] Use of a dibenzylamine compound of any of the above-mentioned [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof for the production of a therapeutic agent or a prophylactic agent for arteriosclerosis.
    [22] The pharmaceutical composition of the above-mentioned [14], which is used in combination with a different therapeutic agent for hyperlipidemia.
    [23] The pharmaceutical composition of the above-mentioned [22], wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
    [24] The pharmaceutical composition of the above-mentioned [23], wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
    [25] The pharmaceutical composition of the above-mentioned [14], which is used in combination with a different therapeutic agent for obesity.
    [26] The pharmaceutical composition of the above-mentioned [25], wherein the different therapeutic agent for obesity is mazindol.
    [27] The pharmaceutical composition of the above-mentioned [14], which is used in combination with a different therapeutic agent for diabetes.
    [28] The pharmaceutical composition of the above-mentioned [27], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
    [29] The pharmaceutical composition of the above-mentioned [28], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
    [30] The pharmaceutical composition of the above-mentioned [14], which is used in combination with a different therapeutic agent for hypertension.
    [31] The pharmaceutical composition of the above-mentioned [30], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
    [32] The pharmaceutical composition of the above-mentioned [31], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
    [33] The therapeutic agent or a prophylactic agent of the above-mentioned [16], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for hyperlipidemia.
    [34] The therapeutic agent or a prophylactic agent of the above-mentioned [33], wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
    [35] The therapeutic agent or a prophylactic agent of the above-mentioned [34], wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
    [36] The therapeutic agent or a prophylactic agent of the above-mentioned [16], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for obesity.
    [37] The therapeutic agent or a prophylactic agent of the above-mentioned [36], wherein the different therapeutic agent for obesity is mazindol.
    [38] The therapeutic agent or a prophylactic agent of the above-mentioned [16], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for diabetes.
    [39] The therapeutic agent or a prophylactic agent of the above-mentioned [38], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
    [40] The therapeutic agent or a prophylactic agent of the above-mentioned [39], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
    [41] The therapeutic agent or a prophylactic agent of the above-mentioned [16], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for hypertension.
    [42] The therapeutic agent or a prophylactic agent of the above-mentioned [41], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
    [43] The therapeutic agent or a prophylactic agent of the above-mentioned [42], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilndipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
    [44] The method of the above-mentioned [17], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for hyperlipidemia.
    [45] The method of the above-mentioned [44], wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
    [46] The method of the above-mentioned [45], wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
    [47] The method of the above-mentioned [17], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for obesity.
    [48] The method of the above-mentioned [47], wherein the different therapeutic agent for obesity is mazindol.
    [49] The method of the above-mentioned [17], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for diabetes.
    [50] The method of the above-mentioned [49], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
    [51] The method of the above-mentioned [50], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
    [52] The method of the above-mentioned [17], which aims at the treatment or prophylaxis of hyperlipidemia and which is used in combination with a different therapeutic agent for hypertension.
    [53] The method of the above-mentioned [52], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
    [54] The method of the above-mentioned [53], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
    [55] The therapeutic agent or a prophylactic agent of the above-mentioned [19], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for hyperlipidemia.
    [56] The therapeutic agent or a prophylactic agent of the above-mentioned [55], wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
    [57] The therapeutic agent or a prophylactic agent of the above-mentioned [56], wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
    [58] The therapeutic agent or a prophylactic agent of the above-mentioned [19], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for obesity.
    [59] The therapeutic agent or a prophylactic agent of the above-mentioned [58], wherein the different therapeutic agent for obesity is mazindol.
    [60] The therapeutic agent or a prophylactic agent of the above-mentioned [19], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for diabetes.
    [61] The therapeutic agent or a prophylactic agent of the above-mentioned [60], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
    [62] The therapeutic agent or a prophylactic agent of the above-mentioned [61], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
    [63] The therapeutic agent or a prophylactic agent of the above-mentioned [19], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for hypertension.
    [64] The therapeutic agent or a prophylactic agent of the above-mentioned [63], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an a blocker.
    [65] The therapeutic agent or a prophylactic agent of the above-mentioned [64], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amnlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
    [66] The method of the above-mentioned [20], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for hyperlipidemia.
    [67] The method of the above-mentioned [66], wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
    [68] The method of the above-mentioned [67], wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
    [69] The method of the above-mentioned [20], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for obesity.
    [70] The method of the above-mentioned [69], wherein the different therapeutic agent for obesity is mazindol.
    [71] The method of the above-mentioned [20], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for diabetes.
    [72] The method of the above-mentioned [71], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
    [73] The method of the above-mentioned [72], wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
    [74] The method of the above-mentioned [20], which aims at the treatment or prophylaxis of arteriosclerosis and which is used in combination with a different therapeutic agent for hypertension.
    [75] The method of the above-mentioned [74], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
    [76] The method of the above-mentioned [75], wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
DETAILED DESCRIPTION OF THE INVENTION
The definition of each substituent used in the present specification is as follows.
The “halogen atom” is a chlorine atom, a bromine atom, a fluorine atom and the like. For R1, R2, R3, R4, R5, R6, R60, R61 or R62, it is preferably a chlorine atom or a fluorine atom, and a preferable halogen atom as a substituent for the C4-10 cycloalkylalkyl group for R7, R8, R11, R12 or R13 is chlorine atom or fluorine atom.
The “C2-6 alkenyl group” is a straight chain or optionally branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-1-butenyl group, 1-isopropylvinyl group, 2,4-pentadienyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2,4-hexadienyl group, 1-methyl-1-pentenyl group and the like, preferably a straight chain or optionally branched alkenyl group having 2 to 4 carbon atoms. Particularly preferred are ethenyl group, isopropenyl group and 2-methyl-2-propenyl group.
The “C1-6 alkyl group” is a straight chain or optionally branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and the like, preferably a straight chain or optionally branched alkyl group having 1 to 4 carbon atoms. Particularly preferred are methyl group, ethyl group and isopropyl group. R20 and R21 are each preferably a methyl group. For R6, R60, R61 or R62, it is preferably a methyl group or an ethyl group, for R7, R8, R11, R12 or R13, it is preferably an ethyl group, a propyl group or a butyl group, and for R9 or R10, it is preferably a methyl group or an ethyl group. A preferable C1-6 allyl group as a substituent for the C4-10 cycloalkylalkyl group for R7, R8, R11, R12 or R13 is a methyl group or an ethyl group. For R14, it is preferably a methyl group or an ethyl group.
The “C1-6 alkyl group optionally substituted by halogen atoms” is the aforementioned C1-6 alkyl group optionally substituted by the aforementioned halogen atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, trifluoromethyl group, 1- or 2-chloroethyl group, 1- or 2-bromoethyl group, 1- or 2-fluoroethyl group, 1-, 2- or 3-chloropropyl group, 1-, 2- or 3-bromopropyl group, 1-, 2- or 3-fluoropropyl group, 1-, 2-, 3- or 4-chlorobutyl group, 1-, 2-, 3- or 4-bromobutyl group, 1-, 2-, 3- or 4-fluorobutyl group and the like, preferably methyl group, ethyl group or trifluoromethyl group. For R1, R2, R3, R4 or R5, it is preferably a methyl group, an ethyl group or a trifluoromethyl group.
The “C1-6 alkoxy group” means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group and hexyloxy group. Preferred are methoxy group, ethoxy group, isopropoxy group, butoxy group and tert-butoxy group, which have 1 to 4 carbon atoms. Particularly preferred are methoxy group and ethoxy group. For R6, R60, R61 or R62, it is preferably a methoxy group, and a preferable C1-6 alkoxy group as a substituent for the C4-10 cycloalkylalkyl group for R7, R8, R11, R12 or R13 is a methoxy group or an ethoxy group.
The “C1-6 alkoxy group optionally substituted by halogen atoms” is the aforementioned C1-6 alkoxy group optionally substituted by the aforementioned halogen atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group, hexyloxy group, trifluoromethoxy group, 1- or 2-chloroethoxy group, 1- or 2-bromoethoxy group, 1- or 2-fluoroethoxy group, 1-, 2- or 3-chloropropoxy group, 1-, 2- or 3-bromopropoxy group, 1-, 2- or 3-fluoropropoxy group, 1-, 2-, 3- or 4-chlorobutoxy group, 1-, 2-, 3- or 4-bromobutoxy group, 1-, 2-, 3- or 4-fluorobutoxy group and the like. Preferred are methoxy group, ethoxy group and trifluoromethoxy group. For R3, R4 or R5, it is preferably a methoxy group, an ethoxy group or a trifluoromethoxy group.
The “C1-6 allylthio group optionally substituted by halogen atoms” is one wherein the C1-6 allylthio group is optionally substituted by the aforementioned halogen atoms, which is exemplified by methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, tert-butylthio group, pentylthio group, tert-pentylthio group, hexylthio group, trifluoromethylthio group, 1- or 2-chloroethylthio group, 1- or 2-bromoethylthio group, 1- or 2-fluoroethylthio group, 1-, 2- or 3-chloropropylthio group, 1-, 2- or 3-bromopropylthio group, 1-, 2- or 3-fluoropropylthio group, 1-, 2-, 3- or 4-chlorobutylthio group, 1-, 2-, 3- or 4-bromobutylthio group, 1-, 2-, 3- or 4-fluobutylthio group and the like, preferably methylthio group, ethylthio group or trifluoromethylthio group. For R3, R4 or R5, it is preferably a methylthio group, an ethylthio group or a trifluoromethylthio group.
The “C4-10 cycloalkylalkyl group” is a C1-3 alkyl group substituted by C3-7 cycloalkyl group. Here, the “C3-7 cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, which is exemplified by cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group. Preferred is cycloalkyl group having 3 to 6 carbon atoms, which is specifically cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group. The “C1-3 alkyl group” means a straight chain or optionally branched alkyl group having 1 to 3 carbon atoms, which is exemplified by methyl group, ethyl group, propyl group and isopropyl group. Preferred are methyl group, ethyl group and propyl group.
Concrete examples of the “C4-10 cycloalkylalkyl group” include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclopentylethyl group (1- or 2-(cyclopentyl)ethyl group), cyclohexylethyl group (1- or 2-(cyclohexyl)ethyl group), cyclopentylpropyl group (1-, 2- or 3-(cyclopentyl)propyl group) and cyclohexylpropyl group (1-, 2- or 3-(cyclohexyl)propyl group). Preferred is cycloalkylalkyl group preferably having 3 to 7 carbon atoms, which is specifically cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group or cyclohexylmethyl group. A preferable C4-10 cycloalkylalkyl group for R7, R8, R11, R12 or R13 is cyclopentylmethyl group, cyclohexylmethyl group or 2-(cyclopentyl)ethyl group.
The “acyl group” includes alkylcarbonyl groups such as acetyl group, propionyl group, butyryl group, pivaloyl group and the like; and arylcarbonyl groups such as benzoyl group, naphthoyl and the like. Preferred is acetyl group. For R6, R60, R61 or R62, it is preferably an acetyl group, a preferable acyl group as a substituent for the C4-10 cycloalkylalkyl group for R7, R8, R11, R12 or R13 is acetyl group.
The “aryl group” is a phenyl group, a naphthyl group, a biphenyl group and the like, with preference given to a phenyl group.
As the “heterocyclic residue”, a 5- to 8-membered aromatic heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, a bicyclic or tricyclic heterocyclic group condensed therewith and the like can be mentioned. Examples thereof include pyrrolyl group (1-, 2- or 3-pyrrolyl group), furyl group (2- or 3-furyl group), thienyl group (2- or 3-thienyl group), imidazolyl group (1-, 2-, 4- or 5-imidazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), isoxazolyl group (3-, 4- or 5-isoxazolyl group), isothiazolyl group (3-, 4- or 5-isothiazolyl group), oxadiazolyl group (1,2,4-oxadiazol-3 or 5-yl group, 1,3,4-oxadiazol-2-yl group, 1,2,5-oxadiazol-3-yl group), thiadiazolyl group (1,2,4-thiadiazol-3 or 5-yl group, 1,3,4-thiadiazol-2-yl group, 1,2,5-thiadiazol-3-yl group), triazolyl group (1,2,4-triazol-1,3,4 or 5-yl group, 1,2,3-triazol-1, 2 or 4-yl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), benzofuryl group (2-, 3-, 4-, 5-, 6- or 7-benzofuryl group), benzothienyl group (2-, 3-, 4-, 5-, 6- or 7-benzothienyl group), benzimidazolyl group (1-, 2-, 4-, 5-, 6- or 7-benzimidazolyl group), benzoxazolyl group (2-, 4-, 5-, 6- or 7-benzoxazolyl group), benzothiazolyl group (2-, 4-, 5-, 6- or 7-benzothiazolyl group), pyridyl group (2-, 3- or 4-pyridyl group), pyridine-1-oxide group (2-, 3- or 4-pyridine-1-oxide group), pyrimidinyl group (2-, 4- or 5-pyrimidinyl group), tetrazolyl group (1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or 5-yl group), quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group) and the like.
As the “homocyclic ring”, for example, an optionally condensed 3- to 7-membered carbon ring such as C6-10 arene (C6-10 aryl) (e.g., benzene (phenyl), naphthalene (naphthyl) and the like), C3-7 cycloalkane (cycloalkyl) (e.g., cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl) etc.), C3-7 cycloalkene (C3-7 cycloalkenyl group) (e.g., cyclopropene (cyclopronyl), cyclobutene (cyclobutenyl), cyclopentene (cyclopentenyl), cyclohexene (cyclohexenyl), cycloheptene (cycloheptenyl) etc.) and the like, and the like are used. The parenthesis following each name of the homocyclic ring shows a homocyclic group corresponding to the homocyclic ring.
As the substituent that the above-mentioned homocyclic ring may have, for example, (1) a C1-6 allyl group optionally substituted by halogens (particularly, C1-6 allyl group substituted by halogens is preferable), (2) a C3-10 cycloalkyl group, (3) a C2-10 alkenyl group, (4) a C2-10 alkynyl group, (5) a C6-10 aryl group, (6) a C7-20 aralkyl group, (7) a nitro group, (8) a hydroxy group, (9) a mercapto group, (10) a oxo group, (11) a thioxo group, (12) a cyano group, (13) a carbamoyl group, (14) a carboxyl group, (15) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group etc.), (16) a sulfo, (17) a halogen atom, (18) a C1-6 alkoxy group, (19) a C6-10 aryloxy group (e.g., phenoxy group etc.), (20) a C1-6 acyloxy group (e.g., acetoxy, propionyloxy), (21) a C1-6 alkylthio group (e.g., methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, tert-butylthio group etc.), (22) a C6-10 arylthio group (e.g., phenylthio group etc.), (23) a C1-6 alkylsulfinyl group (e.g., methylsulfinyl group, ethylsulfinyl group etc.), (24) a C6-10 arylsulfinyl group (e.g., phenylsulfinyl group etc.), (25) a C1-6 alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group etc.), (26) a C6-10 arylsulfonyl group (e.g., phenylsulfonyl group etc.), (27) an amino group, (28) a C1-6 acylamino group (e.g., acetylamino group, propionylamino group etc.), (29) a mono- or di-C1-4 allylamino group (e.g., methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, dimethylamino group, diethylamino group etc.), (30) a C3-8 cycloalkylamino group (e.g., cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group etc.), (31) a C6-10 arylamino group (e.g., anilino etc.), (32) a C1-6 alkanoyl group (e.g., formyl group, acetyl group, hexanoyl group etc.), (33) C6-10 arylcarbonyl group (e.g., benzoyl group etc.), (34) a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like (e.g., 2- or 3-thienyl group, 2- or 3-furyl group, 3-, 4- or 5-pyrazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-isothiazolyl group, 2-, 4- or 5-oxazolyl group, 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolyl group, 1,2,3- or 1,2,4-triazolyl (1,2,4-triazol-1,3,4 or 5-yl group, 1,2,3-triazol-1, 2 or 4-yl group), 1H or 2H-tetrazolyl (1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or 5-yl group), 2-, 3- or 4-pyridyl group, 2-, 4- or 5-pyrimidyl group, 3- or 4-pyridazinyl group, quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group) etc.) and the like can be mentioned. The number of substitution is 1 to 6, preferably 1 to 3, more preferably 1 or 2.
Preferable examples of the “homocyclic ring optionally having a substituent” formed by R3 and R4 or R4 and R5 together with carbon atoms bonded thereto are C3-7 cycloalkane and benzene, and more preferable examples are cyclopentane and cyclohexane.
As the “heterocyclic ring”, a 5- to 8-membered heterocyclic group containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, and a bicyclic or tricyclic heterocyclic group condensed therewith and the like can be mentioned. Specific examples of the heterocyclic ring include (1) a 5-membered heterocyclic ring containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, such as thiophene (thienyl group), furan (furyl group), pyrrole (pyrrolyl group), pyrroline (pyrrolinyl group), pyrrolidine (pyrrolidinyl group), 1,3-dioxole (1,3-dioxolyl group), oxazole (oxazolyl group), thiazole (thiazolyl group), pyrazole (pyrazolyl group), imidazole (imidazolyl group), imidazoline (imidazolinyl group), isoxazole (isoxazolyl group), isothiazole (isothiazolyl group), furazan (furazanyl group), 1,2,3-thiadiazole (1,2,3-thiadiazolyl group), 1,2,5-thiadiazole (1,2,5-thiadiazolyl group), 1,2,3-triazole (1,2,3-triazolyl group), 1,2,3-triazolidine (triazolidinyl group) and the like, (2) a 6-membered heterocyclic ring containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, such as pyridine (pyridyl group), pyrimidine (pyrimidinyl group), thiomorpholine (thiomorpholinyl group), morpholine (morpholinyl group), 1,2,3-triazine, 1,2,4-triazine (triazinyl group), piperidine (piperidinyl group), pyrane (pyranyl group), thiopyrane (thiopyranyl group), 1,4-oxazine (1,4-oxazinyl group), 1,4-dioxane (1,4-dioxanyl group), 1,4-thiazine (1,4-thiazinyl group), 1,3-thiazine (1,3-thiazinyl group), piperazine (piperazinyl group), oxotriazine (oxotriazinyl group), pyridazine (pyridazinyl group), pyrazine (pyrazinyl group) and the like can be mentioned. As the bicyclic or tricyclic condensed heterocyclic ring, a bicyclic or tricyclic condensed heterocyclic ring containing, besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, such as benzofuran (benzofuryl group), benzothiazole (benzothiazolyl group), benzoxazole (benzoxazolyl group), tetrazolo[1,5-b]pyridazine (tetrazolo[1,5-b]pyridazinyl group), triazolo[4,5-b]pyridazine (triazolo[4,5-b]pyridazinyl group), benzimidazole (benzimidazolyl group), quinoline (quinolyl group), isoquinoline (isoquinolyl group), cinnoline (cinnolinyl group), phthalazine (phthalazinyl group), quinazoline (quinazolinyl group), quinoxaline (quinoxalinyl group), indolizine (indolizinyl group), indole (indolyl group), quinolizine (quinolizinyl group), 1,8-naphthyridine (1,8-naphthyridinyl group), pteridine (pteridinyl group), dibenzofuran (dibenzofuranyl group), carbazole (carbazolyl group), acridine (acrydinyl group), phenanthridine (phenanthridinyl group), chromane (chromanyl group), benzoxazine (benzoxazinyl group), phenazine (phenazinyl group), phenothiazine (phenothiazinyl group), phenoxazine (phenoxazinyl group) and the like can be mentioned. The parenthesis following each name of the heterocyclic ring shows a heterocyclic group corresponding to the heterocyclic ring.
As the substituent that the above-mentioned heterocyclic ring may have, for example, (1) a C1-6 allyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a C3-6 cycloalkyl group, (5) a cycloalkenyl group, (6) a C7-11 aralkyl group, (7) a C6-14 aryl group, (8) a C1-6 alkoxy group, (9) a C6-14 aryloxy group (e.g., phenoxy group etc.), (10) a C1-6 alkanoyl group (e.g., formyl group, acetyl group, propionyl group, n-butyryl group, iso-butyryl group etc.), (11) a C6-14 arylcarbonyl group (e.g., benzoyl group etc.), (12) a C1-6 alkanoyloxy group (e.g., formyloxy group, acetyloxy group, propionyloxy group, n-butyryloxy group, iso-butyryloxy group etc.), (13) a C6-14 arylcarbonyloxy group (e.g., benzoyloxy group etc.), (14) a carboxyl group, (15) a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group etc.), (16) a carbamoyl group, (17) a N-mono-C14 alkylcarbamoyl group (e.g., N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-butylcarbamoyl group etc.), (18) an N,N-di-C1-4 alkylcarbamoyl group (e.g., N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N,N-dipropylcarbamoyl group, N,N-dibutylcarbamoyl group etc.), (19) a cyclic aminocarbonyl group (e.g., 1-aziridinylcarbonyl group, 1-azetidinylcarbonyl group, 1-pyrrolizinylcarbonyl group, 1-piperidinylcarbonyl group, N-methylpiperazinylcarbonyl group, morpholinocarbonyl group etc.), (20) a halogen atom, (21) a C1-6 alkyl group optionally substituted by halogen atoms (e.g., chloromethyl group, dichloromethyl group, trifluoromethyl group, trifluoroethyl group etc.), (22) an oxo group, (23) an amidino group, (24) an imino group, (25) an amino group, (26) a mono- or di-C1-4 alkylamino group (e.g., methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group etc.), (27) a 3- to 6-membered cyclic amino group optionally containing, besides carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like (e.g., aziridinyl group, azetidinyl group, pyrrolizinyl group, pyrrolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, imidazolidinyl group, piperidino group, morpholino group, dihydropyridyl group, pyridyl group, N-methylpiperazinyl group, N-ethylpiperazinyl group etc.), (28) a C1-6 alkanoylamino group (e.g., formamide group, acetamide group, trifluoroacetamide group, propionylamide group, butyrylamide group, isobutyrylamide group etc.), (29) a benzamide group, (30) a carbamoylamino group, (31) a N—C1-4 alkylcarbamoylamino group (e.g., N-methylcarbamoylamino group, N-ethylcarbamoylamino group, N-propylcarbamoylamino group, N-isopropylcarbamoylamino group, N-butylcarbamoylamino group etc.), (32) a N,N-di-C1-4 alkylcarbamoylamino group (e.g., N,N-dimethylcarbamoylamino group, N,N-diethylcarbamoylamino group, N,N-dipropylcarbamoylamino group, N,N-dibutylcarbamoylamino group etc.), (33) a C1-3 alkylenedioxy group (e.g., methylenedioxy group, ethylenedioxy group etc.), (34) a —B(OH)2, (35) a hydroxy group, (36) an epoxy group (—O—), (37) a nitro group, (38) a cyano group, (39) a mercapto group, (40) a sulfo group, (41) a sulfino group (42) a phosphono group, (43) a sulfamoyl group, (44) a C1-6 alkylsulfamoyl group (e.g., N-methylsulfamoyl group, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group etc.), (45) a di-C1-6 alkylsulfamoyl group (e.g., N,N-dimethylsulfamoyl group, N,N-diethylsulfamoyl group, N,N-dipropylsulfamoyl group, N,N-dibutylsulfamoyl group etc.), (46) a C1-6 allylthio group (e.g., methylthio group, ethylthio group, propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group, tert-butylthio group etc.), (47) a phenylthio group, (48) a C1-6 alkylsulfinyl group (e.g., methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group etc.), (49) a phenylsulfinyl group, (50) a C1-6 alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group etc.), (51) a phenylsulfonyl group and the like can be mentioned. The number of substitution is 1 to 6, preferably 1 to 3, more preferably 1 or 2.
Preferable examples of the “heterocyclic ring optionally having a substituent” formed by R3 and R4 or R4 and R5 together with carbon atoms bonded thereto are thiophene, furan, pyrrole, pyrroline, oxazole, thiazole, pyrazole, imidazole, imidazoline, isoxazole, isothiazole, furazan, 1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, 1,2,3-triazine, 1,2,4-triazine, 1,2,3-triazolidine, 2,2-difluoro-1,3-dioxole and 2,2,3,3-tetrafluoro-1,4-dioxane.
In the above-mentioned embodiments, the substituent of the “homocyclic ring optionally having substituents” and the substituent of the “heterocyclic ring optionally having substituents” are preferably selected from the group consisting of (1) C1-6 alkyl group optionally substituted by halogen atoms, (2) nitro group, (3) hydroxy group, (4) mercapto group, (5) cyano group, (6) carbamoyl group, (7) carboxyl group, (8) C1-6 alkoxycarbonyl group, (9) sulfo group, (10) halogen atom, (11) C1-6 alkoxy group, (12) C1-6 alkylthio group, (13) C1-6 alkylsulfinyl group, (14) C1-6 alkylsulfonyl group, (15) amino group, (16) mono- or di-C1-4 allylamino group, (17) C1-6 alkanoyl group and (18) C1-6 alkanoyloxy group.
The “pharmaceutically acceptable salt” may be any as long as it forms a nontoxic salt with the aforementioned compound represented by the formula (1). Examples thereof include, but are not limited to, salts with various inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate and the like; salts with organic acids such as formate, acetate, trifluoroacetate, propionate, oxalate, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate, adipate, tartrate, malate, citrate, benzoate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate and the like; sulfonates such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate and the like; salts with acidic amino acid such as aspartate, glutamate and the like; alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as magnesium salt, calcium salt and the like; ammonium salt; salts with organic base such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; salts with amino acid such as lysin salt, arginine salt and the like; and the like. In some cases, the salt may be a water-containing product, hydrate or solvate with alcohol and the like.
In addition, the above-mentioned compound represented by the formula (1) may have various isomers. For example, E form and Z form are present as geometric isomers, and when an asymmetric carbon atom exists, enantiomer and diastereomer as stereoisomers based thereon exist, and a tautomer can exist. Accordingly, the present invention encompasses all of these isomers and mixtures thereof.
The compound of the present invention encompasses prodrug compounds and metabolites.
By the “prodrug compound” is meant a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group and which, after administration to the body, restores to the original compound to show its inherent efficacy, including a complex and a salt free of covalent bond.
As the prodrug compound of the compound represented by the formula (1) of the present invention, a compound wherein the carboxyl group of the compound represented by the formula (1) is modified by ethyl group, pivaloyloxymethyl group, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, phenyl group, o-tolyl group and the like; a compound wherein the hydroxyl group of the compound represented by the formula (1) is modified by acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group or sulfo group; a compound wherein the amino group of the compound represented by the formula (1) is modified by hexylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonyl group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like, and the like can be mentioned.
BEST MODE FOR EMBODYING THE INVENTION
Now, various substituents and substitution sites are described in more detail in the following.
R1 is preferably a C1-6 allyl group optionally substituted by halogen atoms, more preferably a trifluoromethyl group.
R2 is preferably a halogen atom, a C1-6 alkyl group optionally substituted by halogen atoms or a cyano group, more preferably a trifluoromethyl group or a cyano group.
R3 and R4 are each preferably a hydrogen atoms, a halogen atom, a C1-6 allyl group optionally substituted by halogen atoms, a C1-6 alkoxy group optionally substituted by halogen atoms, a C1-6 allylthio group optionally substituted by halogen atoms or R3 and R4 form a homocyclic ring together with carbon atoms bonded thereto.
R5 is preferably a hydrogen atom.
R6 is preferably a hydrogen atom or a C1-6 alkyl group, more preferably a hydrogen atom, a methyl group or an ethyl group.
n is preferably 0, 1 or 2.
Ring B and (R6)n are each preferably
Figure US07807701-20101005-C00008
wherein R60, R61 and R62 are as defined above, more preferably
Figure US07807701-20101005-C00009
wherein R60 and R61 are as defined above.
A is preferably —N(R7)(R8), more preferably that wherein R7 is a C1-6 alkyl group and R8 is a C4-10 cycloalkylalkyl group optionally substituted by —(CH2)r—COOR10 (wherein r and R10 are as defined above) or a C1-6 alkyl group substituted by carboxyl group.
Preferable examples of the compound of the present invention (1) are as follows:
  • 1. N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine,
  • 2. 3-{[N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • 3. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine,
  • 4. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • 5. N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine,
  • 6. N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine hydrochloride,
  • 7. N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine,
  • 8. 5-{N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino}pentanoic acid hydrochloride,
  • 9. methyl trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate,
  • 10. 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • 11. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-ethyl-2H-tetrazol-5-yl)amine,
  • 12. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-[1,2,4]triazol-3-yl)amine,
  • 13. 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-phenylamino}methyl)-5-trifluoromethylbenzonitrile,
  • 14. 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4,5-dimethyl-thiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile,
  • 15. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(thiazol-2-yl)amine hydrochloride,
  • 16. 3-({N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(thiazol-2-yl)amino}methyl)-5-trifluoromethylbenzonitrile hydrochloride,
  • 17. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(oxazol-2-yl)amine hydrochloride,
  • 18. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylthiazol-2-yl)amine hydrochloride,
  • 19. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methylthiazol-2-yl)amine hydrochloride,
  • 20. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4,5-dimethylthiazol-2-yl)amine hydrochloride,
  • 21. 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(5-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • 22. 3-{[N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(4-methylthiazol-2-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • 23. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(4-methyloxazol-2-yl)amine hydrochloride,
  • 24. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisothiazol-5-yl)amine hydrochloride,
  • 25. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methylisoxazol-3-yl)amine hydrochloride,
  • 26. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methylisoxazol-5-yl)amine hydrochloride,
  • 27. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-3-yl)amine hydrochloride,
  • 28. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(1-methyl-1H-pyrazol-4-yl)amine hydrochloride,
  • 29. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]thiadiazol-2-yl)amine hydrochloride,
  • 30. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,3,4]oxadiazol-2-yl)amine hydrochloride,
  • 31. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-3-ylamine hydrochloride,
  • 32. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-pyridin-2-ylamine hydrochloride,
  • 33. N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • 34. 3-{[N-[2-(N′-cyclopentylmethyl-N′-ethylamino)-5-trifluoromethylbenzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile hydrochloride,
  • 35. methyl 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • 36. methyl 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-ylmethyl)-N-ethylamino]pentanoate hydrochloride,
  • 37. methyl 5-[N-(6-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • 38. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 39. 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 40. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 41. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 42. methyl trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • 43. methyl trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • 44. trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 45. trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 46. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(5-methyl-[1,2,4]oxadiazol-3-yl)amine hydrochloride,
  • 47. methyl trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate hydrochloride,
  • 48. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 49. methyl trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylate,
  • 50. trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 51. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 52. trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 53. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 54. trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 55. methyl 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate hydrochloride,
  • 56. 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methyl-isoxazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 57. 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 58. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 59. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 60. trans-4-{[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • 61. N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(3-methyl-[1,2,4]thiadiazol-5-yl)amine,
  • 62. 5-[N-(6-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 63. methyl 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 64. methyl 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 65. 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 66. 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 67. trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 68. trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 69. trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 70. trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • 71. trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 72. trans-4-{[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 73. 2-(5-{N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]amino}tetrazol-2-yl)ethanol hydrochloride,
  • 74. methyl 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 75. methyl 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoate hydrochloride,
  • 76. 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 77. 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-[1,2,4]triazol-3-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 78. 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 79. 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(3-methylisoxazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 80. 5-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 81. 5-[N-(3-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 82. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • 83. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 84. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 85. 5-[N-(2-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 86. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 87. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoic acid hydrochloride,
  • 88. 5-{N-[6-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}pentanoic acid hydrochloride,
  • 89. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]pentanoic acid hydrochloride,
  • 90. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-2,2-dimethylpentanoic acid hydrochloride,
  • 91. 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]hexanoic acid hydrochloride,
  • 92. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 93. trans-4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 94. (1-{2-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]ethyl}cyclopentyl)acetic acid hydrochloride,
  • 95. trans-4-({N-[6-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)indan-5-yl]-N-ethylamino}methyl)cyclohexanecarboxylic acid,
  • 96. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 97. (1-{2-[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]ethyl}cyclopentyl)acetic acid,
  • 98. trans-4-[{N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 99. trans-4-{[N-(3-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-ethyl-2H-tetrazol-5-yl)amino]methyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 100. trans-4-({N-[3-({N′-[3,5-bis(trifluoromethyl)benzyl]-N′-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,
  • 101.1-{3-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl} indan-5-yl)-N-ethylamino]propyl}cyclohexanecarboxylic acid hydrochloride,
  • 102. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid,
  • 103. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 104. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 105. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 106. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 107. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(1-methyl-1H-pyrazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 108. 5-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-3,3-dimethylpentanoic acid hydrochloride,
  • 109. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 110. 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]hexanoic acid hydrochloride,
  • 111. trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 112. 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • 113. 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-3,3-dimethylhexanoic acid hydrochloride,
  • 114. 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-4,4-dimethylpentanoic acid hydrochloride,
  • 115. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 116. 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • 117. 6-[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]-4,4-dimethylhexanoic acid hydrochloride,
  • 118. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 119. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 120. 6-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}indan-5-yl)-N-ethylamino]-5,5-dimethylhexanoic acid hydrochloride,
  • 121. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 122. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-isobutylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 123. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid amide,
  • 124. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid methylamide,
  • 125. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid dimethylamide,
  • 126. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-chlorophenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 127. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 128. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(m-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 129. trans-4-{[N-(2-{[N′-(3,5-dichlorobenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 130. trans-4-{[N-ethyl-N-(2-{[N′-(2-methyl-2H-tetrazol-5-yl)-N′-(3-methyl-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 131. trans-4-{[N-(2-{[N′-(3-chloro-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 132. trans-4-{[N-ethyl-N-(2-{[N′-(2-methyl-2H-tetrazol-5-yl)-N′-(3-nitro-5-trifluoromethylbenzyl)amino]methyl}-4-trifluoromethoxyphenyl)amino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 133. trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 134. trans-(4-{[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2-difluorobenzo[1,3]dioxol-5-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 135. trans-3-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)propionic acid hydrochloride,
  • 136. trans-(4-{[N-(7-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 137. trans-(4-{[N-(7-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 138. trans-2-(4-{[N-(7-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-ethylamino]methyl}cyclohexyl)acetamide hydrochloride,
  • 139. trans-N-[3,5-bis(trifluoromethyl)benzyl]-N-{2-[N′-ethyl-N′-(4-(methoxymethyl)cyclohexylmethyl)amino]-5-trifluoromethoxybenzyl}-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride,
  • 140. trans-2-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)ethanol hydrochloride,
  • 141. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 142. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 143. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 144. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexylmethyl)phosphonic acid,
  • 145. trans-4-{[N-(2-{[N′-(3-bromo-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 146. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 147. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-bromophenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 148. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)methanol hydrochloride,
  • 149. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-methoxyphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 150. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl]methanol hydrochloride,
  • 151. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4,5-dimethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 152. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylthiophenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 153. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-chloro-5-ethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 154. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 155. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methoxy-4-methylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 156. trans-4-({N-[2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-(2,2,2-trifluoroethyl)phenyl]-N-ethylamino}methyl)cyclohexanecarboxylic acid hydrochloride,
  • 157. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 158. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 159. trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-ethylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 160. trans-4-{[N-(2-{[N′-(3-cyano-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid hydrochloride,
  • 161. trans-4-{[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(4-isopropenylphenyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylic acid,
  • 162. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(p-tolyl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid dihydrochloride,
  • 163. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 164. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 165. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 166. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid,
  • 167. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid,
  • 168. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonate,
  • 169. ethyl trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate,
  • 170. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid,
  • 171. trans-(4-{[N-(2-{[N′-(3-methyl-5-trifluoromethylbenzyl)-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid,
  • 172. trans-(4-{[N-(2-{[N′-(3-methyl-5-trifluoromethylbenzyl)-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid,
  • 173. ethyl cis-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate,
  • 174. {4-[2-(2-{[N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)butyl]cyclohexyl}acetic acid and
  • 175. 5-[2-({N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-methyl-2H-tetrazol-5-yl]amino}methyl)-5-methyl-4-trifluoromethylphenoxy]heptanoic acid.
Of the compounds recited above, the compound shown below are particularly preferable.
  • 115. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 118. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 142. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 143. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 154. trans-(4-{[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 157. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 158. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid hydrochloride,
  • 166. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-propylamino]methyl}cyclohexyl)acetic acid,
  • 167. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-methyl-5-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid and
  • 168. trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonate.
The compound of the present invention, a prodrug thereof and a pharmaceutically acceptable salt thereof have superior CETP inhibitory activity in mammals (e.g., human, monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like), and can be used as CETP activity inhibitors. In addition, utilizing the superior CETP inhibitory activity of the compound of the present invention, a prodrug thereof and a pharmaceutically acceptable salt thereof, they are useful as pharmaceutical agents effective for the prophylaxis or treatment of the diseases in which CETP is involved (e.g., hyperlipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, heart ischemia, thrombosis, cardiac infarction, reperfusion injury, angioplasty restenosis, hypertension, diabetic vascular complications, obesity or endotoxemia etc.), particularly as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases.
When the compound represented by the formula (1) of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with a pharmacologically acceptable carrier, excipient, diluent, filler, disintegrant, stabilizer, preservative, buffer, emulsifier, aromatic, coloring agent, sweetening agent, thickening agent, corrigent, dissolution aids, and other additives, which are known per se, specifically water, vegetable oil, alcohol such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydrates such as lactose, starch and the like, magnesium stearate, talc, lanolin, petrolatum and the like, and can be administered orally or parenterally in the form of tablet, pill, powder, granule, suppository, injection, eye drop, liquid, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like.
While the dose of the pharmaceutical agent of the present invention varies depending on the kind and severity of the disease, the compound to be administered and administration route, age, sex and body weight of patients and the like, it is generally about 1-1000 mg, particularly about 50 mg-800 mg in the amount of the compound represented by the formula (1) of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof per day for an adult by oral administration.
The pharmaceutical agent of the present invention may be administered alone or concurrently with a different prophylactic or therapeutic agent for hyperlipidemia and/or a prophylactic or therapeutic agent for arteriosclerotic diseases, or may be used concurrently with a different pharmaceutical agent (e.g., therapeutic agent for obesity, therapeutic agent for diabetes, therapeutic agent for hypertension, therapeutic agent for arteriosclerosis, therapeutic agent for coronary artery disease etc.). Particularly, concurrent use with a different therapeutic agent for hyperlipidemia (statin pharmaceutical agent) is expected to provide an extremely superior synergistic effect of particularly remarkable suppression of blood cholesterol.
As used herein, by “concurrent use” means a combined use of the compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof with a different pharmaceutical agent, such as a therapeutic agent for hyperlipidemia, wherein the mode of use thereof is not particularly limited. For example, it includes both the administration of a pharmaceutical composition containing the compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof and a different pharmaceutical agent, and the simultaneous or staggered administration of respective preparations produced separately without mixing.
While the dose of the different pharmaceutical agent to be used concurrently varies depending on the kind and severity of the disease, administration route, age, sex and body weight of patients and the like, it is generally about 1-1000 mg, particularly about 50 mg-800 mg thereof per day for an adult by oral administration.
As a therapeutic agent for hyperlipidemia to be used concurrently with the pharmaceutical agent of the present invention, statin pharmaceutical agents such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and the like can be mentioned.
As a therapeutic agent for obesity to be used concurrently with the pharmaceutical agent of the present invention, mazindol and the like can be mentioned.
As a therapeutic agent for diabetes to be used concurrently with the pharmaceutical agent of the present invention, insulin preparations, sulfonylureas (e.g., glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide etc.), insulin secretagogues (e.g., nateglinide etc.), sulfonamides (e.g., glybuzole etc.), biguanides (e.g., metformin hydrochloride, buformin hydrochloride etc.), α glucosidase inhibitors (e.g., voglibose, acarbose etc.), insulin sensitizers (e.g., pioglitazone hydrochloride etc.) and the like can be mentioned.
As a therapeutic agent for hypertension to be used concurrently with the pharmaceutical agent of the present invention, loop diuretics (e.g., furosemide sustained-release preparation etc.), angiotensin converting enzyme inhibitors (e.g., captopril, captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine etc.), angiotensin II receptor antagonists (e.g., losartan potassium, candesartan cilexetil etc.), Ca antagonists (e.g., nicardipine hydrochloride, nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine etc.), β blockers (e.g., propranolol hydrochloride, propranolol hydrochloride sustained-release preparation, pindolol, pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride etc.), α,β blockers (e.g., labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride etc.), α blockers (e.g., prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained-release preparation, urapidil, phentolamine mesylate etc.) and the like can be mentioned.
Moreover, the pharmaceutical agent of the present invention can be administered not only to humans but also to other mammals (e.g., monkey, bovine, horse, dog, cat, rabbit, rat, mouse and the like).
Now, one embodiment of the production method of the dibenzylamino compound represented by compound (I) is explained, but the production method of the present invention is not limited to this example.
When the reaction to be mentioned below is carried out, functional groups at positions other than the reaction site may be protected beforehand as necessary and may be deprotected at a suitable stage.
Moreover, the reaction in each step may be carried out according to a conventional method, wherein isolation and purification are performed by appropriately selecting or combining conventional methods, such as crystallization, recrystallization, column chromatography, preparative HPLC and the like.
Conventional Production Method
The production method of the compound represented by the formula (1) is exemplarily shown in the following.
Figure US07807701-20101005-C00010
Figure US07807701-20101005-C00011
wherein R1, R2, R3, R4, R5, R6, A, ring B and n are as defined above, X is a halogen atom and Ph is a phenyl group.
Production Method 1
Step 1-1
This step is directed to a general reductive amination. The compound represented by the formula (2) is reacted with a compound represented by the formula (3) in the presence of a reducing agent in a solvent to give a compound represented by the formula (4).
As the solvent to be used for the reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as acetic acid, N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination. Preferable solvents in this reaction are chloroform and dichloromethane.
As the reducing agent, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like can be mentioned. A preferable reducing agent in this reaction is sodium triacetoxyborohydride.
Step 1-2
This step is directed to a general alkylation. A compound represented by the formula (4) is reacted with a compound represented by the formula (5) in a solvent in the presence of a base to give one of the object compounds, which is represented by the formula (1-a).
As the solvent to be used for the reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is N,N-dimethylformamide.
As the base, for example, alkali metal hydrides (e.g., sodium hydride, potassium hydride etc.); alkali metal alkoxides (e.g., sodium ethoxide, sodium methoxide, potassium tert-butoxide etc.); alkyllithiums (e.g., n-butyllithium, sec-butyllithium etc.); alkali metal amides (e.g., lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide etc.); alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.); alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide etc.); alkali metal phosphates (e.g., sodium phosphate, potassium phosphate etc.); and organic bases (e.g., triethylamine, pyridine, N-methylmorpholine etc.) can be mentioned, with preference given to sodium hydride and potassium tert-butoxide.
The obtained object compound may be subjected to a salt-forming reaction to give a desired salt.
Production Method 2
Step 2-1
This step is directed to a general reductive amination. A compound represented by the formula (6) is reacted with a compound represented by the formula (3) in a solvent in the presence of a reducing agent to give a compound represented by the formula (7).
As the solvent, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination. Preferable solvents in this reaction are dichloromethane and toluene.
As the reducing agent, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium hydride, aluminum hydride and the like can be mentioned. A preferable reducing agent in this reaction is sodium borohydride.
As a different method, the formula (6) is reacted with the formula (3) to once give a Schiff base, which is followed by a reduction. For a reaction to form a Schiff base, azeotropic dehydration may be conducted in a solvent such as benzene, toluene, ethanol and the like without catalyst or in the presence of an acid catalyst such as hydrochloric acid, acetic acid and the like, or a method using a dehydrating agent such as molecular sieves and the like in an aprotic solvent such as methylene chloride, toluene and the like may be employed.
Step 2-2
A compound represented by the formula (8), which is obtained by treating the formula (2) by a general reduction, is reacted with thionyl chloride in a solvent such as toluene, tetrahydrofuran, chloroform and the like to give a compound wherein hydroxyl group of the formula (8) is chlorinated. Next, a similar reaction as in Step 1-2 using the obtained compound and a compound represented by the formula (7) gives one of the object compounds, which is represented by the formula (1-a).
Production Method 3
Step 3-1
This step is directed to a general reductive amination. A compound represented by the formula (2) is reacted with a compound represented by the formula (9) in a solvent in the presence of a reducing agent to give a compound represented by the formula (10).
As the solvent, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is dichloromethane.
As the reducing agent, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like can be mentioned. A preferable reducing agent in this reaction is sodium triacetoxyborohydride.
Step 3-2
This step is directed to a general nucleophilic substitution reaction. In a similar manner as in Step 1-2, a compound represented by the formula (10) is reacted with a compound represented by the formula (11) to give one of the object compounds, which is represented by the formula (1-a).
Besides such method comprising directly reacting a compound having ring B, which is represented by the formula (11), there is a method comprising forming ring B on the nitrogen atom of compound (10) by a known method. As an example of this method, the following production method 3′ and production method 3″ are shown.
Production Method 3′
When
Figure US07807701-20101005-C00012
is
Figure US07807701-20101005-C00013
Step 3′-1
A compound represented by the formula (10) is reacted with compound (12) in a solvent. The obtained residue is reacted with hydrazine hydrate in a solvent in the presence of an acid to give a compound represented by the formula (1-b), which is one of the object compounds.
As the solvent to be used for the first reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is dichloromethane.
As the solvent to be used for the next reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is 1,2-dimethoxyethane.
As the acid to be used for the reaction, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and the like; organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like; and a mixture thereof can be mentioned, with preference given to methanesulfonic acid.
Production Method 3″
When
Figure US07807701-20101005-C00014
is
Figure US07807701-20101005-C00015
Step 3″-1
A compound represented by the formula (10) is reacted with cyanogen bromide in a solvent in the presence of a base, and the obtained residue is reacted with hydroxylamine in a solvent. The obtained residue is reacted with an acylating agent, such as acid chloride represented by the formula (13) and the like, in a solvent to give a compound represented by the formula (1-c), which is one of the object compounds.
As the solvent to be used for the first reaction, for example, alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is methanol.
As the base to be used for the first reaction, for example, alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.); alkali metal phosphates (e.g., sodium phosphate, potassium phosphate etc.); and organic bases (e.g., triethylamine, pyridine, N-methylmorpholine etc.) can be mentioned, with preference given to sodium hydrogen carbonate.
As the solvent to be used for the next reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is dioxane.
As the solvent to be used for the final reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ester solvents such as ethyl acetate, methyl acetate, butyl acetate and the like; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and the like; and the like can be mentioned, which can be used alone or in combination. A preferable solvent in this reaction is pyridine.
In addition, A, B and R1 to R6 may be further subjected to conversion of a functional group according to a known method, after synthesis of compound (I) in the above-mentioned production method.
As a functional group conversion reaction, for example, when the terminal of substituent A is an ester, the obtained compound (1-a) is subjected to a conventional ester hydrolysis, whereby a compound having a carboxyl group as the terminal of substituent A can be easily obtained. As the solvent to be used for this ester hydrolysis reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and the like; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol and the like, and water can be mentioned, which may be used alone or in combination. Similarly, as the base to be used for this ester hydrolysis reaction, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and the like can be mentioned.
In addition, a method exists which comprises, after deprotection of protected hydroxyl group at the terminal of substituent A, conversion to cyano group, carboxyl group and the like.
A compound represented by the formula (2), which is a starting material of the above-mentioned production method, can be produced according to a conventionally known method. In the following, some examples thereof are explained.
Figure US07807701-20101005-C00016
wherein R3, R4, R5 and R7 are as defined above, and —CH2R8a is a group corresponding to the aforementioned R8.
Aniline represented by the formula (15) is reacted with an acid halide and the like in the presence or absence of a base under cooling to heating in an organic solvent, water, or without solvent, whereby a compound represented by the formula (16) can be synthesized (Step 4-1). The compound represented by the formula (16) is reacted with a reducing agent such as lithium aluminum hydride, Red-Al, sodium borohydride and the like under cooling to heating in an organic solvent, whereby a compound represented by the formula (17) can be synthesized (Step 4-2). The compound represented by the formula (17) is reacted with allyl halide and the like in the presence or absence of a base under cooling to heating in an organic solvent or water, or without solvent, whereby a compound represented by the formula (18) can be synthesized (Step 4-3). The compound represented by the formula (18) is reacted using a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-a), which is one of the desired starting materials, can be synthesized (Step 4-4).
Figure US07807701-20101005-C00017
wherein R3, R4, R5, R11, R12 and R13 are as defined above.
Phenol represented by the formula (19) is reacted with alcohol represented by the formula; (R11)(R12)(R3)COH (wherein R11, R12 and R13 are as defined above) in the presence of triphenylphosphine using a condensing agent such as diethyl azodicarboxylate and the like under cooling to heating in an organic solvent or water, or without solvent, whereby a compound represented by the formula (20) can be synthesized (Step 5-1). The compound represented by the formula (20) is reacted using a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-b), which is one of the desired starting materials, can be synthesized (Step 5-2).
Figure US07807701-20101005-C00018
wherein R3, R4, R5, R11 and R12 are as defined above, and X is a halogen atom.
Halobenzene represented by the formula (21) and butyllithium are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with ketone, aldehyde and the like, whereby a compound represented by the formula (22) can be synthesized (Step 6-1). The compound represented by the formula (22) is hydrogenated in the presence of a catalyst such as palladium hydroxide and the like at room temperature or under heating in an organic solvent or water, whereby a compound represented by the formula (23) can be synthesized (Step 6-2). The compound represented by the formula (23) is reacted using a brominating agent such as bromosuccinimide and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (24) can be synthesized (Step 6-3). The compound represented by the formula (24) and butyllithium are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with N,N-dimethylformamide and the like, whereby a compound represented by the formula (2-c), which is one of the desired starting materials, can be synthesized (Step 6-4).
Figure US07807701-20101005-C00019
wherein R3, R4, R5, R7 and R8 are as defined above.
A fluorobenzene compound represented by the formula (25) and LDA, butyllithium and the like are reacted in an organic solvent under cooling to room temperature and a lithio form generated is treated with N,N-dimethylformamide and the like, whereby a compound represented by the formula (26) can be synthesized (Step 7-1). The compound represented by the formula (26) is reacted with an amine represented by the formula; (R7)(R8)NH in the presence of a base such as potassium carbonate and the like under cooling to heating in an organic solvent or without solvent, whereby a compound represented by the formula (2-d), which is one of the desired starting materials, can be synthesized (Step 7-2).
The present invention is explained in more detail in the following by referring to Examples, which are not to be construed as limitative.
EXAMPLES Example 1 N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine
a) N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine
To a solution (10 ml) of 3-(N-cyclopentylmethyl-N-ethylamino)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (333 mg) and 5-amino-2-methyltetrazole (231 mg) in chloroform was added sodium triacetoxyborohydride (745 mg) with stirring at room temperature, and acetic acid (13 μl) was added successively. The reaction solution was stirred overnight and sodium borohydride (50 mg) and methanol (3 ml) were added. The mixture was further stirred for 2 hr. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1→3:1) to give the title compound (254 mg, 59%).
1HNMR (CDCl3, 400 MHz) δ: 1.01 (t, J=7.1 Hz, 3H), 1.10-1.30 (m, 2H), 1.30-1.62 (m, 4H), 1.67-1.82 (m, 6H), 1.93-2.10 (m, 1H), 2.63-2.77 (m, 4H), 2.81 (d, J=7.1 Hz, 2H), 2.94 (q, J=7.1 Hz, 2H), 4.14 (s, 3H), 4.51 (d, J=5.8 Hz, 2H), 5.35-5.50 (brs, 1H), 6.87 (s, 1H), 7.03 (s, 1H).
b) N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-methyl-2H-tetrazol-5-yl)amine
To a solution (2 ml) of N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine (121 mg) obtained in Example 1 a) in N,N-dimethylformamide (DMF) was added sodium hydride (16 mg) with stirring at room temperature. The reaction solution was stirred for 1 hr and 3,5-bis(trifluoromethyl)benzyl bromide (73 μl) was added. The mixture was further stirred overnight. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (102 mg, 52%) (see Table 1).
Example 2 3-{[N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile
a) 3-bromomethyl-5-trifluoromethylbenzonitrile
To a solution (10 ml) of 3-hydroxymethyl-5-trifluoromethylbenzonitrile (1.00 g) and carbon tetrabromide (1.81 g) in dichloromethane was added triphenylphosphine (1.37 g) with stirring under ice-cooling, and the mixture was continuously stirred for 30 min. The reaction solution was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (1.11 g, 84%).
1HNMR (CDCl3, 400 MHz) δ: 4.50 (s, 2H), 7.85 (s, 1H), 7.87 (s, 2H).
b) 3-{[N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-trifluoromethylbenzonitrile
To a solution (2 ml) of N-[3-(N′-cyclopentylmethyl-N′-ethylamino)-5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine (132 mg) obtained in Example 1 a) in DMF was added sodium hydride (17 mg) with stirring at room temperature. The reaction solution was stirred for 1 hr and 3-bromomethyl-5-trifluoromethylbenzonitrile (114 mg) obtained in Example 2b) was added. The mixture was further stirred overnight.
Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1) to give the title compound (86 mg, 44%) (see Table 1).
Example 3 N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine
In a similar manner as in Example 1, the title compound was obtained (see Table 1).
Example 4 N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine hydrochloride
To a solution (12 ml) of N-[3,5-bis(trifluoromethyl)benzyl]-N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-(2-methyl-2H-tetrazol-5-yl)amine (550 mg) obtained in Example 3 in n-hexane was added dropwise 1N hydrochloric acid-diethyl ether (0.76 ml) with stirring at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (332 mg) (see Table 1).
Example 5 N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-(2H-tetrazol-5-yl)-[3,5-bis(trifluoromethyl)benzyl]amine
To a solution (1 ml) of a compound obtained in a similar manner as in Example 1, N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(2-triphenylmethyl-2H-tetrazol-5-yl)amine (75 mg), in ethyl acetate was added dropwise 4N hydrochloric acid-ethyl acetate (3 ml) with stirring at room temperature. The mixture was stirred at room temperature for 1.5 hr and 1N aqueous sodium hydroxide, then aqueous citric acid solution were added. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified using a preparative TLC plate (n-hexane:ethyl acetate=2:1) to give the title compound (24 mg, 46%) (see Table 1).
Example 6 N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine hydrochloride
a) N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine
To a solution (20 ml) of 6-(N-cyclopentylmethyl-N-ethylamino)indane-5-carbaldehyde (1.09 g) and 3,5-bis(trifluoromethyl)benzylamine (1.26 g) in dichloromethane was added sodium triacetoxyborohydride (1.70 g) with stirring at room temperature. The reaction solution was stirred overnight. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1) to give the title compound (1.65 g, 83%).
1HNMR (CDCl3, 300 MHz) δ: 0.95 (t, J=7.1 Hz, 3H), 1.04-1.22 (m, 2H), 1.35-1.78 (m, 6H), 1.90-2.17 (m, 3H), 2.78 (d, J=7.4 Hz, 2H), 2.75-2.95 (m, 6H), 3.84 (s, 2H), 3.88 (s, 2H), 7.07 (s, 1H), 7.12 (s, 1H), 7.75 (s, 1H), 7.83 (s, 2H).
b) N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine
To a solution (3 ml) of N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine (150 mg) obtained in Example 6 a) and 2-chloropyrimidine (69 mg) in toluene was added triethylamine (0.17 ml) with stirring at room temperature. The reaction solution was refluxed with stirring overnight and concentrated. The obtained residue was purified using a preparative TLC plate (n-hexane:ethyl acetate=6:1) to give the title compound (68 mg, 39%).
1HNMR (CDCl3, 400 MHz) δ: 0.92 (t, J=7.1 Hz, 3H), 0.97-1.12 (m, 2H), 1.30-1.60 (m, 6H), 1.83-2.08 (m, 3H), 2.80-2.93 (m, 8H), 4.86 (s, 2H), 5.06 (s, 2H), 6.59 (t, J=4.7 Hz, 1H), 6.91 (s, 1H), 7.04 (s, 1H), 7.66 (s, 2H), 7.71 (s, 1H), 8.36 (d, J=4.7 Hz, 2H).
c) N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine hydrochloride
In a similar manner as in Example 4, the title compound (50 mg) was obtained from N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(pyrimidin-2-yl)amine (68 mg) obtained in Example 6b) (see Table 2).
Example 7 N-[6-(N′-cyclopentylmethyl-N′-ethylamino)indan-5-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl]-(5-methyl-1H-pyrazol-3-yl)amine
To a solution (20 ml) of N-cyclopentylmethyl-N-{6-[[3,5-bis(trifluoromethyl)benzylamino]methyl]indan-5-yl}-ethylamine (500 mg) obtained in Example 6 a) in dichloromethane was added diketene (85 μl) with stirring under ice-cooling. The reaction solution was stirred for 2 hr. The reaction solution was concentrated and a part (250 mg) of the obtained residue was dissolved in dimethoxyethane (0.7 ml) and methanesulfonic acid (0.56 ml) and then hydrazine hydrate (0.21 ml) were added dropwise with stirring under ice-cooling. The reaction solution was stirred at room temperature for 5 days and saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified using a preparative thin layer chromatography (TLC) plate (n-hexane:ethyl acetate=4:1) to give the title compound (58 mg) (see Table 2).
Example 8 5-{N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino}pentanoic acid hydrochloride
a) methyl 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl} indan-5-yl)-N-ethylamino]pentanoate
To a suspension (10 ml) of methyl 5-(N-{6-[N′-(3,5-bis(trifluoromethyl)benzylamino)methyl]indan-5-yl}-N-ethylamino)pentanoate (500 mg) obtained in a similar manner as in Example 6 a) and sodium hydrogen carbonate (160 mg) in methanol was added cyanogen bromide (165 mg) with stirring at room temperature and the stirring was continued for 2 hr.
The reaction solution was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrated was concentrated. The obtained residue was dissolved in 1,4-dioxane (5 ml). Thereto was added aqueous hydroxylamine solution (50%, 0.14 ml) and the mixture was stirred at room temperature for 5 hr. The reaction solution was concentrated and the obtained residue was dissolved in pyridine (10 ml). Acetyl chloride (0.1 ml) was added with stirring under ice-cooling. The stirring was continued at room temperature for 30 min, and at 130° C. for 3 hr. The reaction solution was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (178 mg, 31%).
1HNMR (CDCl3, 300 MHz) δ: 0.88 (t, J=7.0 Hz, 3H), 1.25-1.60 (m, 4H), 1.95-2.10 (m, 2H), 2.20 (t, J=7.3 Hz, 2H), 2.49 (s, 3H), 2.70-2.90 (m, 8H), 4.56 (s, 2H), 4.72 (s, 2H), 6.99 (s, 1H), 7.02 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H).
b) 5-{N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino}pentanoic acid hydrochloride
To a solution (5 ml) of methyl 5-[N-(6-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(5-methyl-[1,2,4]oxadiazol-3-yl)amino]methyl}indan-5-yl)-N-ethylamino]pentanoate (178 mg) obtained in Example 8 a) in tetrahydrofuran-methanol (THF-MeOH 4:1) was added aqueous sodium hydroxide solution (4N, 2 ml) with stirring at room temperature. The reaction solution was stirred overnight and water was added. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=2:1). To a solution (7 ml) of the obtained compound in n-hexane was added dropwise 1N hydrochloric acid-diethyl ether (0.3 ml) with stirring at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (158 mg, 86%) (see Table 2).
Example 9 methyl trans-4-{[N-(2-[{N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate
a) 5-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-methyl-2H-tetrazole
A solution (70 ml) of 3,5-bis(trifluoromethyl)benzaldehyde (6.71 g) and 5-amino-2-methyltetrazole (3.30 g) in toluene was heated under reflux for 4 hr. The reaction solution was concentrated and the obtained residue was dissolved in ethanol (70 ml), and sodium borohydride (2.10 g) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 30 min, and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was recrystallized from isopropanol-water (3:7, 50 ml) to give the title compound.
1HNMR (CDCl3, 300 MHz) δ: 4.16 (s, 3H), 4.66 (d, J=6.3 Hz2H), 4.92 (brs, 1H), 7.79 (s, 1H), 7.83 (s, 2H).
b) methyl trans-4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-4-trifluoromethoxyphenyl)-N-ethylamino]methyl}cyclohexanecarboxylate
To a solution (5 ml) of methyl trans-4-{[N-ethyl-N-(2-hydroxymethyl-4-trifluoromethoxyphenyl)amino]methyl}cyclohexylcarboxylate (330 mg) in chloroform was added thionyl chloride (0.074 ml) with stirring under ice-cooling, and the stirring was continued for 10 min. The reaction solution was treated with aqueous sodium hydrogen carbonate, extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was dissolved in DMF (3 ml). This solution was added dropwise to a solution (3 ml) of 5-[[3,5-bis(trifluoromethyl)benzyl]amino]-2-methyl-2H-tetrazole (331 mg) obtained in Example 9 a) and sodium hydride (51 mg) in DMF with stirring at room temperature. The stirring was continued for 15 min and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (366 mg, 62%) (see Table 2).
Example 169 ethyl trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate
a) 2-fluoro-4-methyl-5-trifluoromethylbenzaldehyde
To a suspension (200 ml) of 5-fluoro-2-iodotoluene (110.6 g) and copper iodide (76.2 g) in N-methylmorpholine was added dropwise methyl fluorosulfonyl(difluoro)acetate (150 g) with stirring at 120° C. over 2 hr. The stirring was continued at the same temperature for 3.5 hr and the reaction solution was distilled under atmospheric pressure to give a yellow liquid. This was diluted with hexane (300 ml) and washed with saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The obtained hexane solution was added dropwise over 1.5 hr to a mixture of tetrahydrofuran (300 ml) and 1.0 M solution (600 ml) of s-butyllithium in hexane, which had been cooled to −78° C. and stirred. The stirring was continued for 1 hr and N,N-dimethylformamide (57 ml) was added dropwise. After completion of the dropwise addition, 2N aqueous hydrochloric acid (600 ml) was added and the mixture was allowed to warm to room temperature. This was extracted with hexane and washed with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated to give the title compound (61.54 g, 52%).
1HNMR (CDCl3, 300 MHz) δ: 2.56 (s, 3H), 7.14 (d, J=10.7 Hz, 1H), 8.15 (d, J=6.8 Hz, 1H), 10.32 (s, 1H).
b) ethyl trans-8 {4-[(N-ethylamino)methyl]cyclohexyl}acetate
b-1) trans-4-(ethoxycarbonylmethyl)cyclohexanecarboxylic acid
To a solution (600 ml) of ethyl 4-oxocyclohexanecarboxylate (150 g) in ethanol was added sodium hydroxide (38.8 g) with stirring at room temperature. The reaction solution was stirred for 1 hr and ethyl diethylphosphonoacetate (192 ml) was added. To this reaction solution was added dropwise 21% sodium ethoxide/ethanol solution (363 ml) with stirring under ice-cooling over 1 hr. The stirring was continued for 1 hr and acetic acid (126 ml) was added. Then ammonium formate (111 g) and palladium carbon (5%, 15 g) were added and the mixture was stirred at 60° C. for 6 hr with heating. The reaction solution was allowed to return to room temperature and insoluble materials were filtered off through celite. The filtrate was concentrated and the obtained residue was diluted with ethyl acetate. The mixture was washed successively with 2N aqueous hydrochloric acid, water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated to give a crudely purified product (180.4 g) of the title compound.
b-2) ethyl trans-[4-(N-ethylcarbamoyl)cyclohexyl]acetate
To a solution (200 ml) of the crudely purified product (180.4 g) of trans-4-(ethoxycarbonylmethyl)cyclohexanecarboxylic acid obtained in b-1) in tetrahydrofuran was added thionyl chloride (74 ml) with stirring at room temperature. The reaction solution was stirred for 3 hr and concentrated to give an acid chloride. A solution (80 ml) of the above-mentioned acid chloride in tetrahydrofuran was added dropwise to tetrahydrofuran (250 ml) and 70% aqueous ethylamine (250 ml) with stirring under ice-cooling. This reaction solution was stirred for 30 min and water (800 ml) was added. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was recrystallized from hexane-ethyl acetate to give the title compound (78.9 g, yield from ethyl 4-oxocyclohexanecarboxylate 37%).
1HNMR (CDCl3, 300 MHz) δ: 0.90-1.10 (m, 2H), 1.13 (t, J=7.3 Hz, 3), 1.25 (t, J=7.1 Hz, 3H), 1.40-1.60 (m, 2H), 1.72-1.95 (m, 5H), 1.99 (m, 1H), 2.19 (d, J=6.8 Hz, 2H), 3.28 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 5.39 (brs, 1H).
b-3) ethyl trans-8 {4-[(N-ethylamino)methyl]cyclohexyl}acetate
To a suspension (800 ml) of ethyl trans-[4-(N-ethylcarbamoyl)cyclohexyl]acetate (100 g) and sodium borohydride (75.2 g) in tetrahydrofuran was added dropwise acetic acid (114 ml) over 1 hr with stirring under reflux, and the reaction solution was further stirred for 2 hr. The reaction solution was quenched by dropwise addition of water (200 ml) with stirring under ice-cooling. 1.5N Aqueous sodium hydroxide (1000 ml) was added. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was dissolved in ethanol (500 ml). 4N Hydrochloric acid-ethyl acetate (125 ml) was added dropwise with stirring at room temperature, and the stirring was continued for 20 hr. The reaction mixture was diluted with ethyl acetate and washed successively with 2N aqueous sodium hydroxide, water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated to give the title compound (81.9 g, 87%).
1HNMR (CDCl3, 300 MHz) δ: 0.82-1.08 (m, 4H), 1.10 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.37 (m, 1H), 1.66-1.88 (m, 5H), 1.99 (m, 1H), 2.18 (d, J=6.8 Hz, 2H), 2.44 (d, J=6.6 Hz, 2H), 2.62 (q, J=7.1 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H).
c) ethyl trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate
c-1) ethyl trans-(4-{[N-ethyl-N-(2-hydroxymethyl-5-methyl-4-trifluoromethylphenyl)amino]methyl}cyclohexyl)acetate p-toluenesulfonate
A solution (470 ml) of 2-fluoro-4-methyl-5-trifluoromethylbenzaldehyde (47.03 g), ethyl trans-{4-[(N-ethylamino)methyl]cyclohexyl}acetate (57.05 g) and potassium carbonate (94.5 g) in toluene was heated under reflux for 48 hr. The reaction solution was allowed to return to room temperature and washed successively with water, aqueous potassium hydrogen sulfate and saturated brine. The organic layer was dried over magnesium sulfate and magnesium sulfate was filtered off. Ethanol (100 ml) was added to the obtained solution and sodium borohydride (4.31 g) was added with stirring at room temperature. The reaction solution was stirred for 1 hr and aqueous ammonium chloride (200 ml) was added to allow for partitioning. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was dissolved in diethyl ether (1060 ml), and p-toluenesulfonic acid hydrate (43.4 g) was added with stirring at room temperature. The stirring was continued for 2 hr. The precipitated crystals were collected by filtration and dried to give the title compound (120 g, 32%).
1HNMR (CDCl3, 300 MHz) δ: 0.70-1.14 (m, 4H), 1.21 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.42 (m, 1H), 1.50-1.78 (m, 4H), 1.93 (m, 1H), 2.09 (d, J=6.7 Hz, 2H), 2.36 (s, 3H), 2.54 (s, 3H), 3.10-4.15 (m, 4H), 4.09 (q, J=7.1 Hz, 2H), 4.85-5.25 (m, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.33 (s, 1H), 7.54 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 11.57 (brs, 1H).
c-2) ethyl trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate
A solution of ethyl trans-(4-{[N-ethyl-N-(2-hydroxymethyl-5-methyl-4-trifluoromethylphenyl)amino]methyl}cyclohexyl)acetate p-toluenesulfonate (120 g) and sodium hydrogen carbonate (32.3 g) in toluene-water (480-480 ml) was stirred at room temperature for 30 min and partitioned. The organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. Magnesium sulfate was filtered off and the resulting solution was added dropwise to a solution (360 ml) of thionyl chloride (17.65 ml) in toluene with stirring under ice-cooling. The stirring was continued at room temperature for 30 min and pyridine (33 ml) was added to the reaction solution. The mixture was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and potassium t-butoxide (27.5 g) was added to a solution (900 ml) of the obtained residue and 5-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-methyl-2H-tetrazole (69.7 g) obtained in Example 9 a) in N,N-dimethylformamide with stirring at room temperature. The stirring was continued for 2 hr and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was purified by column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (118 g, 80%) (see Table 34).
Example 170 trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid
To a solution (326 ml) of ethyl trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetate (118 g) in ethanol was added 4N aqueous sodium hydroxide solution (163 ml) with stirring at room temperature. The reaction solution was stirred at 60° C. for 2 hr and aqueous citric acid was added with stirring under ice-cooling for neutralization. The mixture was extracted with ethyl acetate and the extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=2:1) to give the title compound (104 g, 92%) (see Table 34).
Example 142 trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid hydrochloride
To a solution (1.5 ml) of trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid (130 mg) in ether was added 1N hydrochloric acid-ether (0.20 ml) with stirring at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (128 mg, 94%) (see Table 29).
Example 168 trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid methanesulfonate
To a solution (580 ml) of trans-(4-{[N-(2-{[N′-[3,5-bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H-tetrazol-5-yl)amino]methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino]methyl}cyclohexyl)acetic acid (96.3 g) in ethyl acetate was added methanesulfonic acid (13.56 ml) with stirring at room temperature. The stirring was continued for 15 hr and the precipitated solid was collected by filtration and dried to give an ethyl acetate solvate of methanesulfonate. This was suspended in heptane-ethyl acetate (3:1, 990 ml) and the suspension was stirred with heating at 80° C. for 20 hr, allowed to return to room temperature, filtered and dried to give the title compound (91.0 g, 83%) (see Table 34).
In a similar manner as in Examples 1-9, 142, 168, 169 and 170, the compounds of Examples 10-141 and 143-167 were obtained. These are shown in Tables 1-34 together with Examples 1-9, 142, 168, 169 and 170.
TABLE 1
Example Structural Formula NMR (δ value, 300 MHz)
1
Figure US07807701-20101005-C00020
 		CDCl3: 0.90 (t, J = 7.0 Hz, 3H), 0.98-1.10 (m, 2H), 1.32-1.60 (m, 6H), 1.67-1.82 (m, 4H), 1.90 (m, 1H), 2.53-2.63 (m, 2H), 2.64-2.77 (m, 2H), 2.74 (d, J = 7.5 Hz, 2H), 2.81 (q, J = 7.0 Hz, 2H), 4.17 (s, 3H), 4.67 (s, 2H), 4.82 (s, 2H), 6.79 (s, 1H), 6.82 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H)
2
Figure US07807701-20101005-C00021
 		CDCl3: 0.91 (t, J = 7.0 Hz, 3H), 0.98-1.14 (m, 2H), 1.33-1.62 (m, 6H), 1.68-1.82 (m, 4H), 1.92 (m, 1H), 2.51-2.62 (m, 2H), 2.65-2.77 (m, 2H), 2.76 (d, J = 7.5 Hz, 2H), 2.83 (q, J = 7.0 Hz, 2H), 4.18 (s, 3H), 4.63 (s, 2H), 4.81 (s, 2H), 6.78 (s, 1H), 6.83 (s, 1H), 7.64 (s, 1H), 7.66 (s, 1H), 7.74 (s, 1H)
3
Figure US07807701-20101005-C00022
 		DMSO-d6: 0.81 (t, J = 6.9 Hz, 3H), 0.90-1.10 (m, 2H), 1.20-1.53 (m, 6H), 1.80 (m, 1H), 1.96 (m, 2H), 2.60-2.90 (m, 8H), 4.17 (s, 3H), 4.75 (s, 2H), 4.76 (s, 2H), 6.91 (s, 1H), 7.07 (s, 1H), 7.83 (s, 2H), 7.97 (s, 1H)
4
Figure US07807701-20101005-C00023
 		DMSO-d6: 0.70-1.10 (m, 4.5H), 1.15-1.70 (m, 6.5H), 1.70-2.14 (m, 3H), 2.58-3.00 (m, 6H), 3.35-4.00 (m, 2H), 4.16 (s, 3H), 4.76 (brs, 2H), 4.75-5.10 (m, 2H), 6.91 (brs, 0.5H), 7.07 (brs, 1H), 7.62-8.10 (m, 3.5H)
5
Figure US07807701-20101005-C00024
 		CDCl3: 1.06 (t, J = 7.2 Hz, 3H), 1.00-1.25 (m, 2H), 1.32-1.69 (m, 4H), 1.71-1.90 (m, 2H), 2.06 (m, 2H), 2.19 (m, 1H), 2.76 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.98 (d, J = 6.8 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 4.38 (s, 2H), 5.04 (s, 2H), 6.85 (s, 1H), 7.10 (s, 1H), 7.74 (s, 2H), 7.81 (s, 1H)
TABLE 2
Example Structural Formula NMR (δ value, 300 MHz)
6
Figure US07807701-20101005-C00025
 		DMSO-d6: 0.83 (t, J = 6.9 Hz, 3H), 0.92-1.23 (m, 2H), 1.23-1.60 (m, 6H), 1.86 (m, 1H), 2.01 (m, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 3.00-3.80 (m, 4H), 5.01 (s, 2H), 5.08 (s, 2H), 6.83 (t, J = 4.7 Hz, 1H) 7.09 (s, 1H), 7.52 (brs, 1H), 7.83 (s, 2H), 7.96 (s, 1H), 8.50 (d, J = 4.7 Hz, 2H)
7
Figure US07807701-20101005-C00026
 		CDCl3: 0.90 (t, J = 7.1 Hz, 3H), 1.00-1.15 (m, 2H), 1.30-1.60 (m, 6H), 1.88 (m, 1H), 2.04 (m, 2H), 2.22 (s, 1H), 2.70-2.91 (m, 8H), 4.55 (s, 2H), 4.59 (s, 2H), 5.37 (s, 1H), 7.03 (s, 1H), 7. 12 (s, 1H), 7.71 (s, 3H)
8
Figure US07807701-20101005-C00027
 		DMSO-d6: 0.65-1.05 (m, 5H), 1.05-1.70 (m, 4H), 1.83-2.20 (m, 4H), 2.60-3.00 (m, 4H), 2.46 (s, 3H), 3.00-4.20 (m, 4H), 4.50-5.10 (m, 4H), 6.80-8.10 (m, 5H)
9
Figure US07807701-20101005-C00028
 		CDCl3: 0.70-0.85 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H), 1.10-1.50 (m, 3H), 1.67-1.90 (m, 4H), 2.15 (m, 1H), 2.69 (d, J = 7.2 Hz, 2H), 2.83 (q, J = 7.2 Hz, 2H), 3.64 (s, 3H), 4.20 (s, 3H), 4.68 (s, 2H), 4.83 (s, 2H), 6.96 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.65 (s, 2H), 7.75 (s, 1H)
10
Figure US07807701-20101005-C00029
 		CDCl3: 0.91 (t, J = 6.9 Hz, 3H), 0.95-1.18 (m, 2H), 1.30-1.60 (m, 6H), 1.92 (m, 1H), 2.04 (m, 2H), 2.70-2.92 (m, 8H), 4.19 (s, 3H), 4.64 (s, 2H), 4.85 (s, 2H), 6.96 (s, 1H), 7.04 (s, 1H), 7.66 (s, 2H), 7.75 (s, 1H)
TABLE 3
Example Structural Formula NMR (δ value, 300 MHz)
11
Figure US07807701-20101005-C00030
 		CDCl3: 0.90 (t, J = 6.9 Hz, 3H), 0.95-1.15 (m, 2H), 1.30-1.62 (m, 6H), 1.59 (t, J = 7.2 Hz, 3H), 1.91 (m, 1H), 2.03 (m, 2H), 2.75 (d, J = 7.5 Hz, 2H), 2.70-2.93 (m, 6H), 4.48 (q, J = 7.2 Hz, 2H), 4.66 (s, 2H), 4.86 (s, 2H), 6.99 (s, 1H), 7.04 (s, 1H), 7.66 (s, 2H), 7.71 (s, 1H)
12
Figure US07807701-20101005-C00031
 		CDCl3: 0.88 (t, J = 7.0 Hz, 3H), 0.95-1.10 (m, 2H), 1.30-1.56 (m, 6H), 1.90 (m, 1H), 2.02 (m, 2H), 2.68-2.88 (m, 8H), 3.76 (s, 3H), 4.63 (s, 2H), 4.81 (s, 2H), 7.00 (s, 1H), 7.04 (s, 1H), 7.67 (s, 2H), 7.69 (s, 1H)
13
Figure US07807701-20101005-C00032
 		CDCl3: 0.75-0.95 (m, 1H), 0.95 (t, J = 7.0 Hz, 3H), 1.00-1.20 (m, 2H), 1.30-1.60 (m, 5H), 1.80-2.10 (m, 3H), 2.70-2.93 (m, 8H), 4.65 (s, 2H), 4.70 (s, 2H), 6.67 (d, J = 8.2 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.20 (dd, J = 7.2, 8.2 Hz, 2H), 7.72 (s, 2H), 7.79 (s, 1H)
14
Figure US07807701-20101005-C00033
 		DMSO-d6: 0.84 (t, J = 6.9 Hz, 3H), 0.92-1.12 (m, 2H), 1.25-1.58 (m, 6H), 1.83 (m, 1H), 1.97 (m, 2H), 2.04 (s, 3H), 2.13 (s, 3H), 2.62-2.90 (m, 8H), 4.64 (s, 2H), 4.76 (s, 2H), 6.91 (s, 1H), 7.09 (s, 1H), 7.91 (s, 1H), 7.93 (s, 1H), 8.31 (s, 1H)
15
Figure US07807701-20101005-C00034
 		DMSO-d6: 0.79 (t, J = 6.9 Hz, 3H), 1.02-1.12 (m, 2H), 1.27-1.62 (m, 6H), 1.86-2.05 (m, 3H), 2.75 (t, J =7.3 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H), 3.00-3.70 (m, 4H), 4.92 (s, 2H), 5.02 (s, 2H), 6.90 (d, J = 3.5 Hz, 1H), 7.17 (s, 1H), 7.34 (s, 1H) 7.50 (brs, 1H), 7.83 (s, 1H), 8.00 (s, 1H)
TABLE 4
Example Structural Formula NMR (δ value, 300 MHz)
16
Figure US07807701-20101005-C00035
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 1.00-1.25 (m, 2H), 1.27-1.63 (m, 6H), 1.80-2.10 (m, 3H), 2.78 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 3.00-3.70 (m, 4H), 4.92 (brs, 2H), 4.96 (s, 2H), 6.91 (d, J = 3.7 Hz, 1H), 7.20 (brs, 1H), 7.35 (d, J = 3.7 Hz, 1H), 7.54 (brs, 1H), 7.83 (s, 1H), 8.00 (s, 1H) 8.28 (s, 1H)
17
Figure US07807701-20101005-C00036
 		DMSO-d6: 0.81 (t, J = 7.0 Hz, 3H), 0.95-1.18 (m, 2H), 1.20-1.60 (m, 6H), 1.75-2.10 (m, 3H), 2.75 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.90-3.35 (m, 4H), 4.79 (s, 2H), 4.87 (s, 2H), 7.04 (s, 1H), 7.09 (s, 1H), 7.36 (brs, 1H), 7.65 (s, 1H), 7.86 (s, 2H) 7.99 (s, 1H)
18
Figure US07807701-20101005-C00037
 		DMSO-d6: 0.78 (t, J = 6.9 Hz, 3H), 1.00-1.25 (m, 2H), 1.25-1.70 (m, 6H), 1.85-2.10 (m, 3H), 2.25 (s, 3H), 2.75 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 3.16-3.62 (m, 4H), 4.89 (s, 2H), 4.99 (s, 2H), 7.07 (s, 1H), 7.19 (s, 1H), 7.53 (brs, 1H), 7.82 (s, 2H), 8.02 (s, 1H)
19
Figure US07807701-20101005-C00038
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 0.95-1.20 (m, 2H), 1.20-1.60 (m, 6H), 1.85 (m, 1H), 2.02 (m, 2H), 2.24 (s, 3H), 2.77 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.10-3.60 (m, 4H), 4.92 (s, 2H), 4.99 (s, 2H), 6.50 (s, 1H), 7.17 (s, 1H), 7.57 (brs, 1H), 7.88 (s, 2H), 8.02 (s, 1H)
20
Figure US07807701-20101005-C00039
 		DMSO-d6: 0.79 (t, J = 7.2 Hz, 3H), 0.97-1.20 (m, 2H), 1.20-1.60 (m, 6H), 1.85 (m, 1H), 2.02 (m, 2H), 2.17 (s, 6H), 2.77 (t, J = 7.5 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 3.05-3.60 (m, 4H), 4.90 (s, 2H), 4.98 (s, 2H), 7.15 (s, 1H), 7.54 (brs, 1H), 7.89 (s, 2H), 8.03 (s, 1H)
TABLE 5
Example Structural Formula NMR (δ value, 300 MHz)
21
Figure US07807701-20101005-C00040
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 1.00-1.25 (m, 2H), 1.30-1.65 (m, 6H), 1.82-2.10 (m, 3H), 2.25 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.10-3.60 (m, 4H), 4.88 (s, 2H), 4.92 (s, 2H), 7.06 (s, 1H), 7.20 (s, 1H), 7.52 (brs, 1H), 7.83 (s, 1H), 7.99 (s, 1H), 8.27 (s, 1H)
22
Figure US07807701-20101005-C00041
 		DMSO-d6: 0.82 (t, J = 6.9 Hz, 3H), 0.97-1.20 (m, 2H), 1.25-1.60 (m, 6H), 1.84 (m, 1H), 2.03 (m, 2H), 2.38 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 3.00-3.60 (m, 4H), 4.91 (s, 4H), 6.50 (s, 1H), 7.17 (s, 1H), 7.53 (brs, 1H), 7.88 (s, 1H), 8.02 (s, 1H), 8.28 (s, 1H)
23
Figure US07807701-20101005-C00042
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 0.95-1.15 (m, 2H), 1.20-1.60 (m, 6H), 1.85 (m, 1H), 2.00 (m, 2H), 2.03 (s, 3H), 2.76 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.90-4.00 (m, 4H), 4.76 (s, 2H), 4.84 (s, 2H), 7.10 (s, 1H), 7.39 (m, 2H), 7.86 (s, 2H), 8.00 (s, 1H)
24
Figure US07807701-20101005-C00043
 		DMSO-d6: 0.70-1.15 (m, 5H), 1.20-1.63 (m, 6H), 1.73-2.12 (m, 3H), 2.18 (s, 3H), 2.56-3.00 (m, 6H), 3.25-4.00 (m, 2H), 4.50-5.00 (m, 4H), 6.20 (s, 1H), 6.97 (brs, 1H), 7.11 (brs, 1H), 7.60-8.10 (m, 3H)
25
Figure US07807701-20101005-C00044
 		DMSO-d6: 0.70-1.15 (m, 5H), 1.20-1.70 (m, 6H), 1.71-2.13 (m, 3H), 2.27 (s, 3H), 2.55-3.00 (m, 6H), 3.20-4.00 (m, 2H), 4.40-5.00 (m, 4H), 6.02 (brs, 1H), 6.83-7.35 (m, 2H), 7.85 (s, 2H), 7.98 (s, 1H)
TABLE 6
Example Structural Formula NMR (δ value, 300 MHz)
26
Figure US07807701-20101005-C00045
 		CDCl3: 0.70-1.07 (m, 4.5H), 1.18-1.80 (m, 6.5H), 1.82-2.10 (m, 3H), 2.17 (s, 3H), 2.80-3.00 (m, 4H), 3.00-3.35 (m, 2H), 3.45-4.05 (m, 2H), 4.79 (s, 1H), 4.65-5.70 (m, 4H), 7.03 (s, 1H), 7.32 (brs, 1H), 7.65 (s, 2H), 7.70 (s, 1H)
27
Figure US07807701-20101005-C00046
 		CDCl3: 1.05 (m, 3H), 1.20-1.80 (m, 8H), 2.00 (m, 1H), 2.13 (m, 2H), 2.80-3.30 (m, 4H), 3.10-4.00 (m, 4H), 3.93 (s, 3H), 4.90 (s, 2H), 5.24 (brs, 2H), 5.46 (d, J = 3.3 Hz, 1H), 7.10 (brs, 1H), 7.23 (d, J = 3.3 Hz, 1H), 7.34 (s, 1H), 7.70 (s, 1H), 7.74 (s, 2H)
28
Figure US07807701-20101005-C00047
 		DMSO-d6: 0.93 (m, 3H), 1.10-1.60 (m, 8H), 1.84 (m, 1H), 2.04 (m, 2H), 2.60-3.00 (m, 4H), 3.56 (m, 2H), 3.67 (s, 3H), 4.49 (m, 2H), 4.52 (s, 2H), 5.15 (m, 2H), 7.06 (s, 1H), 7.21 (s, 1H), 7.30 (brs, 1H), 7.71 (brs, 1H), 7.96 (s, 3H)
29
Figure US07807701-20101005-C00048
 		DMSO-d6: 0.85 (t, J = 6.9 Hz, 3H), 1.02-1.20 (m, 2H), 1.30-1.62 (m, 6H), 1.84-2.06 (m, 3H), 2.50 (s, 3H), 2.74 (t, J = 7.3 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.91-3.35 (m, 4H), 4.82 (s, 2H), 4.99 (s, 2H), 7.07 (s, 1H), 7.38 (brs, 2H), 7.89 (s, 2H), 8.01 (s, 1H)
30
Figure US07807701-20101005-C00049
 		DMSO-d6: 0.85 (t, J = 6.9 Hz, 3H), 0.90-1.15 (m, 2H), 1.24-1.56 (m, 6H), 1.82 (m, 1H), 2.00 (m, 2H), 2.33 (s, 3H), 2.77 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.92-3.25 (m, 4H), 4.77 (s, 2H), 4.82 (s, 2H), 7.08 (s, 1H), 7.36 (brs, 1H), 7.92 (s, 2H), 8.01 (s, 1H)
TABLE 7
Example Structural Formula NMR (δ value, 300 MHz)
31
Figure US07807701-20101005-C00050
 		CDCl3: 1.05 (m, 3H), 1.30-1.80 (m, 8H), 1.87-2.22 (m, 3H), 2.75-3.00 (m, 4H), 2.50-4.00 (m, 4H), 4.93 (s, 2H), 4.50-6.00 (m, 2H), 6.93 (brs, 1H), 7.15 (s, 1H), 7.45 (m, 1H), 7.60 (m, 1H), 7.67 (s, 2H), 7.82 (s, 1H), 8.03-8.15 (m, 2H)
32
Figure US07807701-20101005-C00051
 		CDCl3: 1.08 (t, J = 6.9 Hz, 3H), 1.00-1.80 (m, 8H), 1.96-2.20 (m, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 3.20-3.90 (m, 4H), 5.37 (s, 2H), 5.70 (brs, 2H), 6.69 (m, 1H), 6.96 (m, 1H), 7.14 (s, 2H), 7.73 (s, 2H), 7.75 (s, 1H), 7.77 (m, 1H), 8.34 (m, 1H)
33
Figure US07807701-20101005-C00052
 		CDCl3: 0.95-1.23 (m, 5H), 1.30-1.70 (m, 6H), 2.02 (m, 1H), 3.05-3.40 (m, 4H), 4.20 (s, 3H), 4.80 (s, 2H), 5.12 (s, 2H), 7.30 (m, 1H), 7.45 (s, 1H), 7.56 (m, 1H), 7.70 (s, 1H), 7.76 (s, 2H)
34
Figure US07807701-20101005-C00053
 		CDCl3: 0.90-1.25 (m, 5H), 1.30-1.75 (m, 6H), 2.00 (m, 1H), 3.05-3.45 (m, 4H), 4.19 (s, 3H), 4.86 (s, 2H), 5.13 (s, 2H), 7.30 (m, 1H), 7.47 (s, 1H), 7.56 (m, 1H), 7.71 (s, 2H), 7.73 (s, 1H)
35
Figure US07807701-20101005-C00054
 		CDCl3: 0.92-1.25 (m, 4H), 1.40-2.00 (m, 3H), 2.00-2.40 (m, 4H), 2.82 (t, J = 7.4 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 3.05-4.00 (m, 4H), 3.60 (s, 3H), 4.17 (s, 3H), 5.01 (brs, 2H), 5.39 (brs, 2H), 7.06 (brs, 1H), 7.25 (brs, 1H), 8.02 (s, 3H)
TABLE 8
Example Structural Formula NMR (δ value, 300 MHz)
36
Figure US07807701-20101005-C00055
 		CDCl3: 0.88 (m, 3H), 1.25 (m, 1H), 1.42-1.78 (m, 2H), 1.88 (m, 1H), 2.12 (m, 2H), 2.25 (m, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 3.28 (m, 2H), 3.61 (s, 3H), 3.80 (m, 2H), 4.17 (s, 3H), 4.96 (s, 2H), 5.41 (brs, 2H), 7.06 (brs, 1H), 7.24 (brs, 1H), 7.71 (s, 2H), 7.77 (s, 1H)
37
Figure US07807701-20101005-C00056
 		CDCl3: 1.08 (m, 3H), 1.34-1.80 (m, 4H), 2.12 (m, 2H), 2.23 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 3.10-4.00 (m, 4H), 3.60 (s, 3H), 3.86 (s, 3H), 4.79 (brs, 2H), 5.09 (brs, 2H), 5.46 (s, 1H), 7.22 (s, 1H), 7.24 (brs, 1H), 7.30 (s, 1H), 7.70 (s, 1H), 7.73 (s, 2H)
38
Figure US07807701-20101005-C00057
 		CDCl3: 1.07 (m, 3H), 1.27 (m, 1H), 1.42-1.70 (m, 2H), 1.82 (m, 1H), 2.10 (m, 2H), 2.28 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 3.10-3.45 (m, 2H), 3.50-4.00 (m, 2H), 4.17 (s, 3H), 4.99 (s, 2H), 5.33 (brs, 2H), 7.06 (brs, 1H), 7.21 (s, 1H), 7.70 (s, 3H)
39
Figure US07807701-20101005-C00058
 		CDCl3: 1.13 (m, 3H), 1.30 (m, 1H), 1.45-2.20 (m, 3H), 2.12 (m, 2H), 2.31 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H), 3.10-4.00 (m, 4H), 4.17 (s, 3H), 4.94 (s, 2H), 5.35 (brs, 2H), 7.08 (brs, 1H), 7.21 (s, 1H), 7.73 (s, 2H), 7.79 (s, 1H)
40
Figure US07807701-20101005-C00059
 		CDCl3: 1.04 (brt, J = 6.6 Hz, 3H), 1.23 (m, 1H), 1.41-1.66 (m, 2H), 1.79 (m, 1H), 2.13 (m, 2H), 2.17 (s, 3H), 2.24 (t, J = 7.2 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 3.00-4.00 (m, 4H), 4.82 (s, 1H), 4.84 (s, 2H), 5.22 (s, 2H), 7.07 (s, 1H), 7.26 (s, 1H), 7.67 (s, 2H), 7.70 (s, 1H)
TABLE 9
Example Structural Formula NMR (δ value, 300 MHz)
41
Figure US07807701-20101005-C00060
 		CDCl3: 1.04 (brt, J = 6.6 Hz, 3H), 1.18-1.73 (m, 4H), 2.12 (m, 2H), 2.42 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 3.10-4.00 (m, 4H), 3.89 (s, 3H), 4.62 (s, 2H), 4.76 (s, 2H), 5.47 (d, J = 2.2 Hz, 1H), 7.07 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.45 (brs, 1H), 7.66 (s, 2H), 7.74 (s, 1H)
42
Figure US07807701-20101005-C00061
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 0.80-0.97 (m, 2H), 1.02-1.20 (m, 2H), 1.34 (m, 1H), 1.58-1.80 (m, 8H), 2.13 (m, 1H), 2.56 (m, 2H), 2.71 (m, 2H), 2.90-3.70 (m, 4H), 3.55 (s, 3H), 3.73 (s, 3H), 4.58 (s, 2H), 4.69 (s, 2H), 5.63 (s, 1H), 6.97 (s, 1H), 7.30 (brs, 1H), 7.53 (s, 1H), 7.78 (s, 2H), 7.93 (s, 1H)
43
Figure US07807701-20101005-C00062
 		DMSO-d6: 0.82 (t, J = 6.9 Hz, 3H), 0.80-1.00 (m, 2H), 1.04-1.22 (m, 2H), 1.36 (m, 1H), 1.60-1.84 (m, 8H), 2.16 (m, 1H), 2.58 (m, 2H), 2.72 (m, 2H), 2.90-3.70 (m, 4H), 3.56 (s, 3H), 3.73 (s, 3H), 4.58 (s, 2H), 4.62 (s, 2H), 5.61 (s, 1H), 6.99 (s, 1H), 7.30 (brs, 1H), 7.53 (s, 1H), 7.76 (s, 1H), 7.87 (s, 1H), 8.19 (s, 1H)
44
Figure US07807701-20101005-C00063
 		DMSO-d6: 0.79 (t, J = 6.9 Hz, 3H), 0.80-1.01 (m, 2H), 1.03-1.21 (m, 2H), 1.37 (m, 1H), 1.60-1.84 (m, 8H), 2.04 (m, 1H), 2.55 (m, 2H), 2.71 (m, 2H), 3.00-3.60 (m, 4H), 3.74 (s, 3H), 4.59 (s, 2H), 4.70 (s, 2H), 5.63 (s, 1H), 6.97 (s, 1H), 7.32 (brs, 1H), 7.54 (s, 1H), 7.78 (s, 2H), 7.93 (s, 1H)
45
Figure US07807701-20101005-C00064
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 0.80-1.01 (m, 2H), 1.04-1.21 (m, 2H), 1.37 (m, 1H), 1.60-1.85 (m, 8H), 2.05 (m, 1H), 2.58 (m, 2H), 2.72 (m, 2H), 3.00-3.60 (m, 4H), 3.74 (s, 3H), 4.59 (s, 2H), 4.63 (s, 2H), 5.62 (s, 1H), 7.00 (s, 1H), 7.33 (brs, 1H), 7.55 (s, 1H), 7.75 (s, 1H), 7.87 (s, 1H), 8.19 (s, 1H)
TABLE 10
Example Structural Formula NMR (δ value, 300 MHz)
46
Figure US07807701-20101005-C00065
 		CDCl3: 0.70-2.20 (m, 14H), 2.49 (brs, 3H), 2.60-4.20 (m, 8H), 4.40-6.00 (m, 4H), 6.70-7.50 (m, 2H), 7.68 (s, 3H)
47
Figure US07807701-20101005-C00066
 		DMSO-d6: 0.80 (t, J = 7.3 Hz, 3H), 0.70-1.00 (m, 2H), 1.00-1.20 (m, 2H), 1.34 (m, 1H), 1.60-1.80 (m, 4H), 1.99 (m, 2H), 2.12 (m, 1H), 2.73 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 2.90-3.70 (m, 4H), 3.54 (s, 3H), 3.69 (s, 3H), 4.58 (s, 2H), 4.66 (s, 2H), 5.58 (s, 1H), 7.12 (s, 1H), 7.36 (brs, 1H), 7.49 (s, 1H), 7.80 (s, 2H), 7.92 (s, 1H)
48
Figure US07807701-20101005-C00067
 		DMSO-d6: 0.70-1.00 (m, 5H), 1.00-1.20 (m, 2H), 1.34 (m, 1H), 1.60-1.80 (m, 4H), 1.90-2.10 (m, 3H), 2.73 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.90-4.20 (m, 4H), 3.70 (s, 3H), 4.59 (s, 2H), 4.67 (s, 2H), 5.59 (s, 1H), 7.12 (s, 1H), 7.40 (brs, 1H), 7.50 (s, 1H), 7.80 (s, 2H), 7.92 (s, 1H)
49
Figure US07807701-20101005-C00068
 		CDCl3: 0.63-0.93 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 1.12-1.42 (m, 3H), 1.70-1.93 (m, 4H), 2.04 (m, 2H), 2.14 (m, 1H), 2.68 (d, J = 7.3 Hz, 2H), 2.70-2.92 (m, 6H), 3.64 (s, 3H), 3.73 (s, 3H), 4.52 (s, 2H), 4.54 (s, 2H), 5.43 (s, 1H), 7.01 (s, 1H), 7.12 (s, 1H), 7.13 (s, 1H), 7.72 (s, 2H), 7.75 (s, 1H)
50
Figure US07807701-20101005-C00069
 		DMSO-d6: 0.80 (t, J = 6.9 Hz, 3H), 0.80-1.00 (m, 2H), 1.00-1.22 (m, 2H), 1.37 (m, 1H), 1.57-1.84 (m, 4H), 1.92-2.12 (m, 3H), 2.77 (t, J = 8.0 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H), 3.00-3.55 (m, 4H), 3.72 (s, 3H), 4.63 (s, 4H), 5.60 (s, 1H), 7.16 (s, 1H), 7.49 (brs, 1H), 7.52 (s, 1H), 7.77 (s, 1H), 7.89 (s, 1H), 8.19 (s, 1H)
TABLE 11
Example Structural Formula NMR (δ value, 300 MHz)
51
Figure US07807701-20101005-C00070
 		DMSO-d6: 0.55-2.20 (m, 15H), 2.40-3.80 (m, 8H), 4.16 (s, 3H), 4.50-5.20 (m, 4H), 6.91, 7.07, 7.60-8.12 (m, 5H)
52
Figure US07807701-20101005-C00071
 		DMSO-d6: 0.60-2.20 (m, 15H), 2.40-3.80 (m, 8H), 4.15 (s, 3H), 4.00-5.20 (m, 4H), 6.70-7.30, 7.60-8.40 (m, 5H)
53
Figure US07807701-20101005-C00072
 		DMSO-d6: 0.60-1.40 (m, 8H), 1.60-1.85 (m, 4H), 1.85-2.15 (m, 3H), 2.05 (s, 3H), 2.50-3.00 (m, 8H), 4.62 (s, 2H), 4.68 (s, 2H), 5.11 (s, 1H), 6.93 (s, 1H), 7.08 (s, 1H), 7.83 (s, 2H), 7.99 (s, 1H)
54
Figure US07807701-20101005-C00073
 		DMSO-d6: 0.60-1.22 (m, 7H), 1.30 (m, 1H), 1.60-1.84 (m, 4H), 1.87-2.15 (m, 3H), 2.05 (s, 3H), 2.40-3.00 (m, 8H), 4.62 (s, 4H), 5.10 (s, 1H), 6.93 (s, 1H), 7.08 (s, 1H), 7.84 (s, 1H), 7.93 (s, 1H), 8.24 (s, 1H)
55
Figure US07807701-20101005-C00074
 		CDCl3: 1.11 (brt, J = 6.9 Hz, 3H), 1.30-1.90 (m, 4H), 2.13 (m, 2H), 2.25 (m, 2H), 2.83-3.00 (m, 4H), 3.20-3.80 (m, 4H), 3.60 (s, 3H), 3.81 (s, 3H), 4.77 (s, 2H), 5.08 (brs, 2H), 5.44 (s, 1H), 7.16 (brs, 1H), 7.17 (s, 1H), 7.33 (s, 1H), 7.73 (s, 1H), 7.77 (s, 1H), 7.81 (s, 1H)
TABLE 12
Example Structural Formula NMR (δ value, 300 MHz)
56
Figure US07807701-20101005-C00075
 		CDCl3: 1.05 (m, 3H), 1.05-1.40 (m, 2H), 1.42-1.96 (m, 2H), 2.16 (s, 3H), 2.16 (m, 2H), 2.27 (m, 2H), 2.70-3.05 (m, 4H), 3.00-4.00 (m, 4H), 4.79 (s, 3H), 5.22 (s, 2H), 7.08 (s, 1H), 7.26 (s, 1H), 7.70 (s, 1H), 7.76 (s, 2H)
57
Figure US07807701-20101005-C00076
 		CDCl3: 1.08 (brt, J = 6.9 Hz, 3H), 1.25-1.70 (m, 4H), 2.14 (m, 2H), 2.38 (m, 2H), 2.89 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 3.30-4.00 (m, 4H), 3.90 (s, 3H), 4.71 (s, 2H), 4.92 (s, 2H), 5.49 (s, 1H), 7.15 (s, 1H), 7.36 (s, 2H), 7.73 (s, 1H), 7.77 (s, 1H), 7.81 (s, 1H)
58
Figure US07807701-20101005-C00077
 		CDCl3: 0.97 (m, 3H), 1.27-1.80 (m, 4H), 2.13 (m, 2H), 2.20-2.75 (m, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.97 (t, J = 7.3 Hz, 2H), 3.10-4.00 (m, 4H), 3.86 (s, 3H), 4.80 (s, 4H), 6.90 (s, 1H), 7.30 (s, 1H), 7.67 (s, 2H), 7.73 (s, 1H), 8.88 (s, 1H)
59
Figure US07807701-20101005-C00078
 		DMSO-d6: 0.80 (t, J = 7.0 Hz, 3H), 0.70-1.00 (m, 2H), 1.00-1.23 (m, 2H), 1.40 (m, 1H), 1.58-1.82 (m, 4H), 1.92-2.12 (m, 3H), 2.74 (t, J = 7.0 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 3.14 (m, 2H), 3.31 (m, 2H), 3.71 (s, 3H), 4.75 (s, 2H), 4.80 (s, 2H), 7.09 (s, 1H), 7.46 (s, 1H), 7.82 (s, 2H), 7.93 (s, 1H), 8.26 (s, 1H)
60
Figure US07807701-20101005-C00079
 		CDCl3: 0.63-0.90 (m, 2H), 0.87 (t, J = 7.0 Hz, 3H), 1.15-1.55 (m, 3H), 1.70-1.95 (m, 4H), 2.03 (m, 2H), 2.16 (m, 1H), 2.66 (d, J = 7.0 Hz, 2H), 2.67-2.92 (m, 6H), 3.77)s, 3H), 4.56 (s, 2H), 4.79 (s, 2H), 7.00 (s, 2H), 7.67 (s, 2H), 7.72 (s, 1H), 7.75 (s, 1H)
TABLE 13
Example Structural Formula NMR (δ value, 300 MHz)
61
Figure US07807701-20101005-C00080
 		CDCl3: 0.90 (m, 3H), 0.90-1.20 (m, 2H), 1.32-1.70 (m, 6H), 1.90 (m, 1H), 2.06 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.65-3.00 (m, 8H), 4.68 (s, 2H), 4.80 (s, 2H), 6.94 (s, 1H), 7.06 (s, 1H), 7.67 (s, 2H), 7.76 (s, 1H)
62
Figure US07807701-20101005-C00081
 		CDCl3: 1.02 (m, 3H), 1.30-1.74 (m, 4H), 2.15 (m, 2H), 2.26-2.68 (m, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 3.20-4.40 (m, 4H), 3.86 (s, 3H), 4.79 (s, 2H), 4.95 (s, 2H), 7.02 (s, 1H), 7.31 (s, 1H), 7.72 (s, 1H), 7.78 (s, 1H), 7.80 (s, 1H), 8.90 (s, 1H)
63
Figure US07807701-20101005-C00082
 		CDCl3: 1.12 (t, J = 6.6 Hz, 3H), 1.30-2.00 (m, 8H), 2.25 (m, 2H), 2.67 (m, 2H), 2.76 (m, 2H), 3.20-3.80 (m, 4H), 3.60 (s, 3H), 3.95 (s, 3H), 4.86 (s, 2H), 5.33 (brs, 2H), 5.51 (d, J = 2.3 Hz, 1H), 6.98 (brs, 1H), 7.11 (s, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.72 (s, 3H)
64
Figure US07807701-20101005-C00083
 		CDCl3: 1.15 (t, J = 6.9 Hz, 3H), 1.30-2.00 (m, 8H), 2.27 (m, 2H), 2.69 (m, 2H), 2.77 (m, 2H), 3.20-3.80 (m, 4H), 3.61 (s, 3H), 3.93 (s, 3H), 4.86 (s, 2H), 5.22 (brs, 2H), 5.52 (d, J = 2.5 Hz, 1H), 6.99 (brs, 1H), 7.08 (s, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.74 (s, 1H), 7.76 (s, 1H), 7.82 (s, 1H)
65
Figure US07807701-20101005-C00084
 		CDCl3: 1.04 (m, 3H), 1.30-1.88 (m, 8H), 2.42 (m, 2H), 2.65 (m, 2H), 2.80 (m, 2H), 3.30-4.00 (m, 4H), 3.96 (s, 3H), 4.70 (s, 2H), 4.85 (s, 2H), 5.52 (s, 1H), 6.89 (s, 1H), 7.26 (s, 1H), 7.41 (s, 1H), 7.67 (s, 2H), 7.75 (s, 1H)
TABLE 14
Example Structural Formula NMR (δ value, 300 MHz)
66
Figure US07807701-20101005-C00085
 		CDCl3: 1.08 (m, 3H), 1.30-1.88 (m, 8H), 2.38 (m, 2H), 2.69 (m, 2H), 2.81 (m, 2H), 3.30-4.00 (m, 4H), 3.94 (s, 3H), 4.74 (s, 2H), 4.90 (s, 2H), 5.52 (s, 1H), 6.94 (s, 1H), 7.26 (s, 1H), 7.44 (s, 1H), 7.73 (s, 1H), 7.78 (s, 1H), 7.79 (s, 1H)
67
Figure US07807701-20101005-C00086
 		DMSO-d6: 0.60-0.90 (m, 2H), 0.80 (m, 3H), 1.00-1.20 (m, 2H), 1.26 (m, 1H), 1.55-1.80 (m, 8H), 1.99 (m, 1H) 2.40-3.80 (m, 8H), 4.16 (s, 3H), 4.74 (s, 4H), 6.73 (s, 1H), 6.85 (s, 1H), 7.80 (s, 2H), 7.95 (s, 1H)
68
Figure US07807701-20101005-C00087
 		DMSO-d6: 0.60-0.90 (m, 2H), 0.82 (t, J = 6.9 Hz, 3H), 1.00-1.40 (m, 3H), 1.58-1.85 (m, 8H), 2.02 (m, 1H), 2.40-3.80 (m, 8H), 4.16 (s, 3H), 4.68 (s, 2H), 4.73 (s, 2H), 6.72 (s, 1H), 6.84 (s, 1H), 7.80 (s, 1H), 7.84 (s, 1H) 8.19 (s, 1H)
69
Figure US07807701-20101005-C00088
 		DMSO-d6: 0.80 (m, 3H), 0.80-1.00 (m, 2H), 1.01-1.23 (m, 2H), 1.42 (m, 1H), 1.57-1.804 (m, 8H), 2.04 (m, 1H), 2.54 (m, 2H), 2.71 (m, 2H), 3.23 (m, 2H), 3.43 (m, 2H), 3.71 (s, 3H), 4.73 (s, 2H), 4.82 (s, 2H), 6.93 (s, 1H), 7.36 (s, 1H), 7.81 (s, 2H), 7.93 (s, 1H), 8.30 (s, 1H)
70
Figure US07807701-20101005-C00089
 		CDCl3: 0.65-1.00 (m, 2H), 0.87 (t, J = 7.0 Hz, 3H), 1.15-1.50 (m, 3H), 1.65-2.00 (m, 8H), 2.17 (m, 1H), 2.58 (m, 2H), 2.66 (d, J = 7.3 Hz, 2H), 2.69 (m, 2H), 2.80 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 4.56 (s, 2H), 4.73 (s, 2H), 6.79 (s, 1H), 6.82 (s, 1H), 7.66 (s, 2H), 7.72 (s, 1H), 7.74 (s, 1H)
TABLE 15
Example Structural Formula NMR (δ value, 300 MHz)
71
Figure US07807701-20101005-C00090
 		DMSO-d6: 0.65-0.90 (m, 2H), 0.81 (t, J = 7.0 Hz, 3H), 1.00-1.25 (m, 2H), 1.25 (m, 1H), 1.58-1.80 (m, 8H), 2.00 (m, 1H), 2.05 (s, 3H), 2.40-2.80 (m, 8H), 4.59 (s, 2H), 4.68 (s, 2H), 5.11 (s, 1H), 6.75 (s, 1H), 6.86 (s, 1H), 7.82 (s, 2H), 7.99 (s, 1H)
72
Figure US07807701-20101005-C00091
 		DMSO-d6: 0.65-0.90 (m, 2H), 0.82 (brt, J = 6.9 Hz, 3H), 1.00-1.30 (m, 2H), 1.30 (m, 1H), 1.60-1.82 (m, 8H), 2.04 (m, 1H), 2.05 (s, 3H), 2.40-2.80 (m, 8H), 4.59 (s, 2H), 4.61 (s, 2H), 5.09 (s, 1H), 6.73 (s, 1H), 6.85 (s, 1H), 7.82 (s, 1H), 7.90 (s, 1H), 8.23 (s, 1H)
73
Figure US07807701-20101005-C00092
 		DMSO-d6: 0.70-1.70 (m, 11H), 1.70-2.11 (m, 3H), 2.60-3.00 (m, 6H), 3.30-4.60 (m, 6H), 4.71, 4.77, 4.88, 4.97 (s, 4H), 6.93, 7.06, 7.11, 7.74 (s, 2H), 7.83, 7.97, 8.00, 8.03 (s, 3H)
74
Figure US07807701-20101005-C00093
 		CDCl3: 1.03 (m, 3H), 1.20-1.86 (m, 8H), 2.23 (m, 2H), 2.62 (m, 2H), 2.77 (m, 2H), 3.10-4.00 (m, 4H), 3.59 (s, 3H), 3.80 (s, 3H), 4.88 (s, 2H), 5.02 (brs, 2H), 6.96 (s, 1H), 7.01 (brs, 1H), 7.69 (s, 3H), 8.39 (brs, 1H)
75
Figure US07807701-20101005-C00094
 		CDCl3: 1.10 (m, 3H), 1.20-1.86 (m, 8H), 2.26 (m, 2H), 2.65 (m, 2H), 2.78 (m, 2H), 3.10-4.00 (m, 4H), 3.61 (s, 3H), 3.80 (s, 3H), 4.87 (s, 2H), 5.16 (brs, 2H), 7.02 (brs, 1H), 7.02 (s, 1H), 7.72 (s, 2H), 7.79 (s, 1H), 8.28 (brs, 1H)
TABLE 16
Example Structural Formula NMR (δ value, 300 MHz)
76
Figure US07807701-20101005-C00095
 		CDCl3: 0.97 (m, 3H), 1.30-1.90 (m, 8H), 2.25-2.95 (m, 2H), 2.60 (m, 2H), 2.80 (m, 2H), 3.20-4.50 (m, 4H), 3.86 (s, 3H), 4.77 (s, 2H), 4.78 (s, 2H), 6.68 (s, 1H), 7.13 (s, 1H), 7.66 (s, 2H), 7.75 (s, 1H), 8.90 (brs, 1H)
77
Figure US07807701-20101005-C00096
 		CDCl3: 1.03 (m, 3H), 1.30-1.90 (m, 8H), 2.20-2.70 (m, 2H), 2.66 (m, 2H), 2.81 (m, 2H), 3.20-4.40 (m, 4H), 3.88 (s, 3H), 4.78 (s, 2H), 4.93 (s, 2H), 6.81 (s, 1H), 7.12 (s, 1H), 7.71 (s, 1H), 7.79 (s, 2H), 9.01 (brs, 1H)
78
Figure US07807701-20101005-C00097
 		CDCl3: 1.05 (m, 3H), 1.12-1.90 (m, 8H), 2.16 (s, 3H), 2.25 (m, 2H), 2.67 (m, 2H), 2.76 (m, 2H), 3.25 (m, 2H), 3.45-4.00 (m, 2H), 4.82 (s, 3H), 5.17 (brs, 2H), 6.91 (brs, 1H), 7.07 (s, 1H), 7.67 (s, 2H), 7.72 (s, 1H)
79
Figure US07807701-20101005-C00098
 		CDCl3: 1.10 (m, 3H), 1.13-1.90 (m, 8H), 2.16 (s, 3H), 2.28 (m, 2H), 2.69 (m, 2H), 2.77 (m, 2H), 3.00-4.00 (m, 4H), 4.78 (s, 2H), 4.82 (s, 1H), 5.16 (brs, 2H), 6.93 (brs, 1H), 7.05 (s, 1H), 7.70 (s, 1H), 7.77 (s, 2H)
80
Figure US07807701-20101005-C00099
 		CDCl3: 1.09 (m, 3H), 1.27 (m, 1H), 1.40-1.95 (m, 7H), 2.28 (t, J = 7.3 Hz, 2H), 2.60 (m, 2H), 2.76 (m, 2H), 3.30 (m, 2H), 3.50-3.90 (m, 2H), 4.17 (s, 3H), 4.98 (brs, 2H), 5.28 (brs, 2H), 6.91 (brs, 1H), 7.02 (s, 1H), 7.71 (s, 3H)
TABLE 17
Example Structural Formula NMR (δ value, 300 MHz)
81
Figure US07807701-20101005-C00100
 		CDCl3: 1.00-1.43 (m, 4H), 1.43-1.96 (m, 7H), 2.30 (t, J = 7.3 Hz, 2H), 2.63 (m, 2H), 2.77 (m, 2H), 3.32 (m, 2H), 3.55-3.95 (m, 2H), 4.17 (s, 3H), 4.93 (s, 2H), 5.29 (brs, 2H), 6.94 (brs, 1H), 7.02 (s, 1H), 7.74 (s, 2H), 7.80 (s, 1H)
82
Figure US07807701-20101005-C00101
 		CDCl3: 0.62-0.92 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.94 (m, 7H), 2.07 (m, 2H), 2.17 (m, 1H), 2.49 (s, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.70-2.90 (m, 6H), 4.58 (s, 2H), 4.77 (s, 2H), 6.98 (s, 1H), 7.02 (s, 1H), 7.62 (s, 2H), 7.73 (s, 1H)
83
Figure US07807701-20101005-C00102
 		CDCl3: 1.08 (m, 3H), 1.40-1.80 (m, 4H), 2.32 (m, 2H), 3.30-4.00 (m, 4H), 3.90 (s, 3H), 4.78 (s, 2H), 5.12 (brs, 2H), 5.54 (s, 1H), 7.16 (s, 1H), 7.33 (m, 1H), 7.35 (s, 1H), 7.63 (m, 1H), 7.73 (s, 3H)
84
Figure US07807701-20101005-C00103
 		CDCl3: 1.01 (m, 3H), 1.33-1.70 (m, 4H), 2.31 (t, J = 7.0 Hz, 2H), 2.70-4.00 (m, 4H), 3.87 (s, 3H), 4.68 (s, 2H), 4.84 (s, 2H), 5.53 (s, 1H), 7.26 (s, 1H), 7.46 (m, 1H), 7.54 (s, 1H), 7.60 (m, 1H), 7.70 (s, 2H), 7.74 (s, 1H)
85
Figure US07807701-20101005-C00104
 		CDCl3: 1.05 (m, 3H), 1.36-1.70 (m, 4H), 2.31 (t, J = 7.0 Hz, 2H), 2.60-4.00 (m, 4H), 3.84 (s, 3H), 4.68 (s, 2H), 4.82 (s, 2H), 5.49 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.39 (m, 1H), 7.56 (s, 1H), 7.58 (m, 1H), 7.73 (s, 1H), 7.78 (s, 2H)
TABLE 18
Example Structural Formula NMR (δ value, 300 MHz)
86
Figure US07807701-20101005-C00105
 		CDCl3: 1.08 (m, 3H), 1.40-1.70 (m, 4H), 2.29 (m, 2H), 3.10-3.80 (m, 4H), 4.18 (s, 3H), 4.90 (s, 2H), 5.19 (s, 2H), 7.34 (m, 1H), 7.49 (s, 1H), 7.60 (m, 1H), 7.74 (s, 3H)
87
Figure US07807701-20101005-C00106
 		DMSO-d6: 0.80-1.70 (m, 7H), 1.42 (t, J = 7.3 Hz, 3H), 1.80-2.24 (m, 4H), 2.60-3.05, 3.30-4.20 (m, 8H), 4.48 (q, J = 7.3 Hz, 2H), 4.55-5.10 (m, 4H), 6.85-7.20, 7.60-8.13 (m, 5H)
88
Figure US07807701-20101005-C00107
 		DMSO-d6: 0.70-1.70 (m, 7H), 1.84-2.22 (m, 4H), 2.60-3.00, 3.30-4.40 (m, 8H), 4.48 (t, J = 5.4 Hz, 2H), 4.60-5.10 (m, 4H), 6.86-8.13 (m, 5H)
89
Figure US07807701-20101005-C00108
 		DMSO-d6: 0.85 (brt, J = 6.6 Hz, 3H), 1.18-1.50 (m, 4H), 2.10 (t, J = 7.0 Hz, 2H), 2.65-3.10 (m, 4H), 4.14 (s, 3H), 4.60-4.98 (m, 4H), 6.90 (s, 1H), 7.05-7.45 (m, 2H), 7.86 (s, 2H), 7.94 (s, 1H)
90
Figure US07807701-20101005-C00109
 		CDCl3: 1.05 (s, 9H), 1.15-1.60 (m, 3H), 1.86 (m, 1H), 2.10 (m, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 3.28 (m, 2H), 3.30-4.00 (m, 2H), 4.17 (s, 3H), 5.00 (s, 2H), 5.37 (s, 2H), 7.07 (s, 1H), 7.19 (s, 1H), 7.70 (s, 3H)
TABLE 19
Example Structural Formula NMR (δ value, 300 MHz)
91
Figure US07807701-20101005-C00110
 		CDCl3: 1.06 (m, 3H), 1.00-1.70 (m, 5H), 1.86 (m, 1H), 2.11 (m, 2H), 2.26 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 3.00-3.40 (m, 2H), 3.50-3.90 (m, 2H), 4.17 (s, 3H), 4.98, 5.03 (brs, 2H), 5.37 (brs, 2H), 7.03 (brs, 1H), 7.22 (s, 1H), 7.67 (s, 1H), 7.69 (s, 2H)
92
Figure US07807701-20101005-C00111
 		CDCl3: 0.96 (brs, 6H), 1.10 (m, 3H), 1.28 (m, 1H), 1.86 (m, 1H), 2.10 (m, 2H), 2.18 (s, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 3.38 (m, 2H), 3.78 (m, 2H), 4.16 (s, 3H), 4.99 (s, 2H), 5.35 (s, 2H), 7.10 (s, 1H), 7.21 (s, 1H), 7.69 (s, 3H)
93
Figure US07807701-20101005-C00112
 		DMSO-d6: 0.56-1.45 (m, 8H), 1.44 (t, J = 7.2 Hz, 3H), 1.52-2.10 (m, 7H), 2.50-3.80 (m, 8H), 4.49 (q, J = 7.2 Hz, 2H), 4.71 (s, 2H), 4.79 (s, 2H), 6.92 (s, 1H), 7.08 (s, 1H), 7.80 (s, 2H), 7.95 (s, 1H)
94
Figure US07807701-20101005-C00113
 		CDCl3: 1.00-2.00 (m, 12H), 2.10 (m, 1H), 2.00-2.70 (m, 3H), 2.80 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.7 Hz, 2H), 3.10-4.00 (m, 4H), 4.16 (s, 3H), 5.00 (s, 2H), 5.34 (brs, 2H), 7.13 (s, 1H), 7.22 (brs, 1H), 7.67 (s, 3H)
95
Figure US07807701-20101005-C00114
 		CDCl3: 0.67-0.90 (m, 2H), 0.88 (t, J = 7.0 Hz, 3H), 1.15-1.96 (m, 7H), 2.04 (m, 2H), 2.20 (m, 1H), 2.66 (d, J = 6.8 Hz, 2H), 2.70-2.92 (m, 6H), 4.12 (m, 2H), 4.59 (m, 2H), 4.69 (s, 2H), 4.86 (s, 2H), 6.96 (s, 1H), 7.04 (s, 1H), 7.64 (s, 2H), 7.73 (s, 1H)
TABLE 20
Example Structural Formula NMR (δ value, 300 MHz)
96
Figure US07807701-20101005-C00115
 		DMSO-d6: 0.68-0.95 (m, 2H), 0.90 (t, J = 6.9 Hz, 3H), 1.00-1.24 (m, 2H), 1.32 (m, 1H), 1.63-1.85 (m, 4H), 2.02 (m, 1H), 2.80 (d, J = 6.9 Hz, 2H), 2.89 (q, J = 6.9 Hz, 2H), 4.17 (s, 3H), 4.80 (s, 2H), 4.82 (s, 2H), 7.22 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.83 (s, 2H), 7.95 (s, 1H)
97
Figure US07807701-20101005-C00116
 		CDCl3: 0.91 (t, J = 7.0 Hz, 3H), 1.30-1.46 (m, 2H), 1.46-1.65 (m, 10H), 1.68-1.85 (m, 4H), 2.23 (s, 2H), 2.59 (m, 2H), 2.71 (m, 2H), 2.80-2.98 (m, 4H), 4.18 (s, 3H), 4.66 (s, 2H), 4.76 (s, 2H), 6.81 (s, 1H), 6.83 (s, 1H), 7.67 (s, 2H), 7.73 (s, 1H)
98
Figure US07807701-20101005-C00117
 		DMSO-d6: 0.66-0.90 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H), 1.00-1.40 (m, 3H), 1.60-1.80 (m, 4H), 2.01 (m, 1H), 2.69 (m, 2H), 2.81 (m, 2H), 4.16 (s, 3H), 4.80 (s, 2H), 4.84 (s, 2H), 6.90 (s, 1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.88 (s, 2H), 7.96 (s, 1H)
99
Figure US07807701-20101005-C00118
 		DMSO-d6: 0.55-2.15 (m, 17H), 1.44 (m, 3H), 2.40-2.90 (m, 6H), 3.36, 3.58 (m, 2H), 4.49 (q, J = 7.3 Hz, 2H), 4.74 (s, 2H), 4.93, 4.95 (s, 2H), 6.74, 6.85, 6.90, 7.55 (s, 2H), 7.79 (s, 1H), 7.95 (s, 2H)
100
Figure US07807701-20101005-C00119
 		DMSO-d6: 0.55-2.15 (m, 17H), 2.40-2.90 (m, 6H), 3.34, 3.57 (m, 2H), 3.83 (m, 2H), 4.49 (m, 2H), 4.72, 4.73 (s, 2H), 4.91, 4.98 (s, 2H), 6.75, 6.83, 6.92, 7.55 (s, 2H), 7.80 (s, 1H), 7.95 (s, 2H)
TABLE 21
Example Structural Formula NMR (δ value, 300 MHz)
101
Figure US07807701-20101005-C00120
 		CDCl3: 0.90-1.65 (m, 14H), 1.70-2.00 (m, 3H), 2.10 (m, 2H), 2.81 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.4 H, 2H), 3.00-4.00 (m, 4H), 4.18 (s, 3H), 4.98 (brs, 2H), 5.37 (brs, 2H), 7.09 (brs, 1H), 7.18 (s, 1H), 7.68 (s, 1H), 7.70 (s, 2H)
102
Figure US07807701-20101005-C00121
 		CDCl3: 0.88 (t, J = 6.9 Hz, 3H), 1.00 (s, 6H), 1.52 (m, 2H), 2.04 (m, 2H), 2.13 (s, 2H), 2.73-2.97 (m, 8H), 3.77 (s, 3H), 4.52 (s, 2H), 4.57 (s, 2H), 5.44 (s, 1H), 7.01 (s, 1H), 7.08 (s, 1H), 7.11 (s, 1H), 7.71 (s, 3H)
103
Figure US07807701-20101005-C00122
 		CDCl3: 0.98 (s, 6H), 1.08 (m, 3H), 1.31 (m, 1H), 1.83 (m, 1H), 2.10 (m, 2H), 2.17 (s, 2H), 2.50 (s, 3H), 2.82 (m, 2H), 2.93 (m, 2H), 3.05-4.10 (m, 4H), 4.94 (s, 2H), 5.30 (s, 2H), 7.07 (s, 1H), 7.18 (brs, 1H), 7.66 (s, 3H)
104
Figure US07807701-20101005-C00123
 		DMSO-d6: 0.88 (s, 6H), 0.88 (m, 3H), 1.32 (m, 2H), 2.04 (s, 2H), 2.60-3.70 (m, 4H), 4.16 (s, 3H), 4.84 (brs, 2H), 4.86 (s, 2H), 6.97 (s, 1H), 7.07-7.60 (m, 2H), 7.87 (S, 2H), 7.97 (s, 1H)
105
Figure US07807701-20101005-C00124
 		DMSO-d6: 0.89 (s, 6H), 0.89 (m, 3H), 1.35 (m, 1H), 2.05 (s, 2H), 2.82-3.20 (m, 4H), 4.17 (s, 3H), 4.77 (s, 2H), 4.82 (s, 2H), 7.28 (s, 1H), 7.29 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.81 (s, 2H), 7.94 (s, 1H)
TABLE 22
Example Structural Formula NMR (δ value, 300 MHz)
106
Figure US07807701-20101005-C00125
 		CDCl3: 0.75-1.10 (m, 5H), 1.10-1.55 (m, 3H), 1.60-2.00 (m, 4H), 2.18 (m, 1H), 2.80-3.60 (m, 4H), 3.84 (s, 3H), 4.73 (s, 2H), 4.77 (s, 2H), 5.42 (s, 1H), 7.06-7.30 (m, 3H), 7.19 (d, J = 2.1 Hz, 1H), 7.73 (s, 2H), 7.74 (s, 1H)
107
Figure US07807701-20101005-C00126
 		DMSO-d6: 0.86 (s, 6H), 0.91 (t, J = 6.9 Hz, 3H), 1.33 (m, 2H), 2.04 (s, 2H), 3.20-3.55 (m, 4H), 3.71 (s, 3H), 4.70 (s, 2H), 4.74 (s, 2H), 5.61 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.72 (m, 1H), 7.83 (s, 2H), 7.92 (s, 1H)
108
Figure US07807701-20101005-C00127
 		CDCl3: 1.00 (s, 6H), 1.15 (m, 3H), 1.20-2.00 (m, 2H), 2.19 (s, 2H), 2.48 (s, 3H), 3.00-4.00 (m, 4H), 4.94 (s, 2H), 5.32 (s, 2H), 7.10 (s, 1H), 7.20-7.60 (m, 2H), 7.74 (s, 1H), 7.77 (s, 2H)
109
Figure US07807701-20101005-C00128
 		DMSO-d6: 0.62-0.90 (m, 2H), 0.84 (t, J = 6.9 Hz, 3H), 1.00-1.25 (m, 2H), 1.28 (m, 1H), 1.60-1.83 (m, 4H), 2.00 (m, 1H), 2.50 (s, 3H), 2.67 (d, J = 6.6 Hz, 2H), 2.80 (q, J = 6.9 Hz, 2H), 4.73 (s, 2H), 4.74 (s, 2H), 6.90 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.86 (s, 2H), 7.97 (s, 1H)
110
Figure US07807701-20101005-C00129
 		DMSO-d6: 0.85 (m, 6H), 1.06-1.35 (m, 4H), 1.40 (m, 2H), 2.09 (t, J = 7.2 Hz, 2H), 2.60-3.60 (m, 4H), 4.16 (s, 3H), 4.78 (s, 2H), 4.84 (s, 2H), 6.93 (s, 1H), 7.08-7.40 (m, 2H) 7.87 (s, 2H), 7.95 (s, 1H)
TABLE 23
Example Structural Formula NMR (δ value, 300 MHz)
111
Figure US07807701-20101005-C00130
 		DMSO-d6: 0.57-2.14 (m, 15H), 1.97 (d, J = 6.6 Hz, 2H), 2.40-3.80 (m, 8H), 4.16 (s, 3H), 4.60-5.20 (m, 4H), 6.91, 7.07, 7.60-8.10 (m, 5H)
112
Figure US07807701-20101005-C00131
 		DMSO-d6: 0.60-1.65 (m, 13H), 1.80-2.16 (m, 4H), 2.60-4.30 (m, 8H), 4.15 (s, 3H), 4.60-5.10 (m, 4H), 6.86-7.10, 7.64-8.10 (m, 5H)
113
Figure US07807701-20101005-C00132
 		DMSO-d6: 0.79 (s, 6H), 0.96 (m, 3H), 0.83-1.74 (m, 4H), 1.82-2.16 (m, 4H), 2.60-3.00 (m, 6H), 3.40-3.78 (m, 2H), 4.14 (s, 3H), 4.60-5.10 (m, 4H), 6.90-7.20, 7.60-8.07 (m, 5H)
114
Figure US07807701-20101005-C00133
 		CDCl3: 0.69 (brs, 6H), 0.95 (m, 3H), 1.44 (m, 2H), 2.07 (brs, 2H), 2.18 (m, 2H), 2.50-3.40 (m, 8H), 4.19 (s, 3H), 4.81 (s, 2H), 4.97 (brs, 2H), 6.98 (s, 1H), 7.10 (s, 1H), 7.71 (s, 1H), 7.73 (s, 2H)
115
Figure US07807701-20101005-C00134
 		DMSO-d6: 0.63-0.85 (m, 4H), 0.83 (t, J = 6.9 Hz, 3H), 1.22 (m, 1H), 1.47 (m, 1H), 1.45-1.73 (m, 4H), 1.98 (d, J =6.7 Hz, 2H), 2.67 (d, J = 6.5 Hz, 2H), 2.79 (q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 4.77 (s, 2H), 4.81 (s, 2H), 6.87 (s, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.84 (s, 2H), 7.95 (s, 1H)
TABLE 24
Example Structural Formula NMR (δ value, 300 MHz)
116
Figure US07807701-20101005-C00135
 		CDCl3: 0.85 (s, 6H), 1.11 (m, 3H), 1.27 (m, 2H), 1.55 (m, 2H), 2.27 (m, 2H), 3.10-3.90 (m, 4H), 4.18 (s, 3H), 4.97 (s, 2H), 5.33 (s, 2H), 7.12 (s, 1H), 7.10-7.40 (m, 2H), 7.74 (s, 1H), 7.78 (s, 2H)
117
Figure US07807701-20101005-C00136
 		CDCl3: 0.88 (s, 6H), 1.12 (m, 3H), 1.27 (m, 2H), 1.57 (m, 2H), 2.29 (m, 2H), 3.00-4.00 (m, 4H), 4.19 (s, 3H), 4.99 (s, 2H), 5.36 (s, 2H), 7.26 (m, 1H), 7.52 (s, 1H), 7.70 (m, 1H), 7.74 (s, 1H), 7.77 (s, 2H)
118
Figure US07807701-20101005-C00137
 		DMSO-d6: 0.63-0.85 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H), 1.24 (m, 1H), 1.47 (m, 1H), 1.40-1.73 (m, 4H), 1.97 (d, J = 6.9 Hz, 2H), 2.76 (d, J = 6.7 Hz, 2H), 2.86 (q, J = 6.9 Hz, 2H), 4.14 (s, 3H), 4.77 (s, 2H), 4.78 (s, 2H), 7.18 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.78 (s, 2H), 7.92 (s, 1H)
119
Figure US07807701-20101005-C00138
 		CDCl3: 0.70-2.00 (m, 13H) 3.00-3.85 (m, 4H), 3.36 (d, J = 6.1 Hz, 2H), 4.17 (s, 3H), 4.98 (s, 2H), 5.37 (brs, 2H), 7.05-7.45 (m, 2H), 7.14 (s, 1H), 7.74 (s, 1H), 7.76 (s, 2H)
120
Figure US07807701-20101005-C00139
 		CDCl3: 0.82 (brs, 6H), 0.94 (m, 3H), 0.80-1.75 (m, 4H), 2.09 (m, 2H), 2.21 (m, 2H), 2.81 (m, 2H), 2.90 (m, 2H), 2.88-3.80 (m, 4H), 4.19 (s, 3H), 4.60-5.90 (m, 4H), 7.14 (brs, 2H), 7.70 (s, 3H)
TABLE 25
Example Structural Formula NMR (δ value, 300 MHz)
121
Figure US07807701-20101005-C00140
 		DMSO-d6: 0.65-0.85 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H), 1.04-1.18 (m, 2H), 1.18-1.37 (m, 3H), 1.60-1.78 (m, 4H), 1.99 (m, 1H), 2.60-2.80 (m, 4H), 4.14 (s, 3H), 4.77 (s, 2H), 4.82 (s, 2H), 6.87 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.86 (s, 2H), 7.96 (s, 1H)
122
Figure US07807701-20101005-C00141
 		DMSO-d6: 0.65-0.85 (m, 2H), 0.74 (t, J = 6.5 Hz, 3H), 1.05-1.20 (m, 2H), 1.58 (m, 1H), 1.60 (m, 1H), 1.62-1.80 (m, 4H), 1.98 (m, 1H), 2.57 (d, J = 7.1 Hz, 2H), 2.59 (d, J = 7.9 Hz, 2H), 4.14 (s, 3H), 4.77 (s, 2H), 4.85 (s, 2H), 6.86 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz,1H), 7.89 (s, 2H), 7.98 (s, 1H)
123
Figure US07807701-20101005-C00142
 		CDCl3: 0.70-0.90 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 1.27-1.52 (m, 3H), 1.71-1.86 (m, 4H), 2.02 (m, 1H), 2.69 (d, J = 7.0 Hz, 2H), 2.84 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 4.69 (s, 2H), 4.83 (s, 2H), 5.19 (s, 1H), 5.33 (s, 1H), 6.96 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.66 (s, 2H), 7.76 (s, 1H)
124
Figure US07807701-20101005-C00143
 		CDCl3: 0.67-0.90 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 1.22-1.50 (m, 3H), 1.72-1.82 (m, 4H), 1.92 (m, 1H), 2.68 (d, J = 7.0 Hz, 2H), 2.79 (d, J = 4.7 Hz, 3H), 2.83 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 4.68 (s, 2H), 4.82 (s, 2H), 5.34 (m, 1H), 6.96 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.65 (s, 2H), 7.75 (s, 1H)
125
Figure US07807701-20101005-C00144
 		CDCl3: 0.70-0.85 (m, 2H), 0.88 (t, J = 7.0 Hz, 3H), 1.30-1.70 (m, 5H), 1.70-1.82 (m, 2H), 2.38 (m, 1H), 2.67 (d, J = 7.0 Hz, 2H), 2.85 (q, J = 7.0 Hz, 2H), 2.92 (s, 3H), 3.00 (s, 3H), 4.20 (s, 3H), 4.67 (s, 2H), 4.82 (s, 2H), 6.96 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.66 (s, 2H), 7.74 (s, 1H)
TABLE 26
Example Structural Formula NMR (δ value, 300 MHz, DMSO-d6)
126
Figure US07807701-20101005-C00145
 		0.70-1.00 (m, 2H), 0.91 (t, J = 6.9 Hz, 3H), 1.05-1.30 (m, 2H), 1.36 (m, 1H), 1.65-1.90 (m, 4H), 2.04 (m, 1H), 2.76 (d, J = 6.6 Hz, 2H), 2.88 (q, J = 6.9 Hz, 2H), 4.72 (s, 2H), 4.91 (s, 2H), 6.64 (d, J = 9.0 Hz, 2H), 6.94 (s, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.89 (s, 2H), 7.99 (s, 1H)
127
Figure US07807701-20101005-C00146
 		0.75-0.95 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H), 1.06-1.25 (m, 2H), 1.34 (m, 1H), 1.70-1.83 (m, 4H), 2.02 (m, 1H), 2.12 (s, 3H), 2.74 (d, J = 7.0 Hz, 2H), 2.89 (q, J = 7.0 Hz, 2H), 4.65 (s, 2H), 4.84 (s, 2H), 6.52 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.88 (s, 2H), 7.96 (s, 1H)
128
Figure US07807701-20101005-C00147
 		0.75-0.95 (m, 2H), 0.90 (t, J = 6.9 Hz, 3H), 1.06-1.25 (m, 2H), 1.33 (m, 1H), 1.66-1.82 (m, 4H), 2.01 (m, 1H), 2.12 (s, 3H), 2.74 (d, J = 5.3 Hz, 2H), 2.86 (q, J = 6.9 Hz, 2H), 4.67 (s, 2H), 4.86 (s, 2H), 6.41 (m, 1H), 6.46 (s, 1H), 6.47 (m, 1H), 6.95 (s, 1H), 6.97 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.88 (s, 2H), 7.96 (s, 1H)
129
Figure US07807701-20101005-C00148
 		0.68-0.90 (m, 2H), 0.86 (t, J = 6.9 Hz, 3H), 1.07-1.23 (m, 2H), 1.31 (m, 1H), 1.62-1.85 (m, 4H), 2.03 (m, 1H), 2.69 (d, J = 5.1 Hz, 2H), 2.82 (q, J = 6.9 Hz, 2H), 4.14 (s, 3H), 4.61 (s, 2H), 4.72 (s, 2H), 6.90 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.22 (s, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H)
130
Figure US07807701-20101005-C00149
 		0.62-0.85 (m, 2H), 0.83 (t, J = 6.7 Hz, 3H), 1.03-1.19 (m, 2H), 1.27 (m, 1H), 1.60-1.78 (m, 4H), 2.00 (m, 1H), 2.30 (s, 3H), 2.66 (d, J = 6.1 Hz, 2H), 2.78 (q, J = 6.7 Hz, 2H), 4.14 (s, 3H), 4.66 (s, 2H), 4.71 (s, 2H), 6.89 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.31 (s, 1H), 7.39 (s, 1H)
TABLE 27
Example Structural Formula NMR (δ value, 300 MHz, DMSO-d6)
131
Figure US07807701-20101005-C00150
 		0.67-0.85 (m, 2H), 0.85 (t, J = 6.9 Hz, 3H), 1.05-1.22 (m, 2H), 1.30 (m, 1H), 1.60-1.80 (m, 4H), 2.01 (m, 1H), 2.68 (m, 2H), 2.81 (q, J = 6.9 Hz, 2H), 4.14 (s, 3H), 4.71 (s, 2H), 4.74 (s, 2H), 6.89 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.56 (s, 1H), 7.70 (s, 1H)
132
Figure US07807701-20101005-C00151
 		0.67-0.85 (m, 2H), 0.85 (t, J = 6.9 Hz, 3H), 1.02-1.20 (m, 2H), 1.29 (m, 1H), 1.62-1.80 (m, 4H), 2.00 (m, 1H), 2.79 (d, J = 6.3 Hz, 2H), 2.81 (q, J = 6.9 Hz, 2H), 4.14 (s, 3H), 4.79 (s, 2H), 4.85 (s, 2H), 6.90 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 8.33 (s, 1H), 8.35 (s, 1H)
133
Figure US07807701-20101005-C00152
 		0.55-0.80 (m, 4H), 0.80 (t, J = 6.9 Hz, 3H), 1.02-1.32 (m, 2H), 1.47-1.78 (m, 4H), 2.61 (d, J = 6.6 Hz, 2H), 2.75 (q, J = 6.9 Hz, 2H), 3.11 (d, J = 6.3 Hz, 2H), 4.17 (s, 3H), 4.78 (s, 2H), 4.81 (s, 2H), 7.01 (s, 1H), 7.35 (s, 1H), 7.81 (s, 2H), 7.95 (s, 1H)
134
Figure US07807701-20101005-C00153
 		0.60-0.80 (m, 4H), 0.78 (t, J = 6.9 Hz, 3H), 1.15 (m, 1H), 1.45 (m, 1H), 1.45-1.68 (m, 4H), 1.97 (d, J = 6.8 Hz, 2H), 2.58 (d, J = 6.5 Hz, 2H), 2.72 (q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 4.75 (s, 2H), 4.79 (s, 2H), 7.00 (s, 1H), 7.34 (s, 1H), 7.79 (s, 2H), 7.93 (s, 1H)
135
Figure US07807701-20101005-C00154
 		0.56-0.75 (m, 4H), 0.84 (t, J = 6.9 Hz, 3H), 1.02 (m, 1H), 1.22 (m, 1H), 1.30 (m, 2H), 1.45-1.70 (m, 4H), 2.12 (d, J = 7.6 Hz, 2H), 2.65 (m, 2H), 2.79 (m, 2H), 4.15 (s, 3H), 4.77 (s, 2H), 4.80 (s, 2H), 6.89 (s, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.84 (s, 2H), 7.96 (s, 1H)
TABLE 28
Example Structural Formula NMR (δ value, 300 MHz)
136
Figure US07807701-20101005-C00155
 		CDCl3: 0.70-0.92 (m, 2H), 1.06 (m, 3H), 0.94-1.17 (m, 2H), 1.36 (m, 1H), 1.47 (m, 1H), 1.61-1.82 (m, 4H), 3.19 (m, 2H), 3.37 (m, 2H), 3.38 (d, J = 6.0 Hz, 2H), 4.19 (s, 3H), 4.94 (s, 2H), 5.22 (brs, 2H), 7.06 (brs, 1H), 7.08 (s, 1H), 7.73 (s, 3H)
137
Figure US07807701-20101005-C00156
 		CDCl3: 0.70-1.18 (m, 4H), 1.03 (m, 3H), 1.45 (m, 1H), 1.55-1.82 (m, 5H), 2.16 (d, J = 6.7 Hz, 2H), 3.07 (m, 2H), 3.24 (m, 2H), 4.19 (s, 3H), 4.89 (s, 2H), 5.11 (s, 2H), 7.02 (brs, 1H), 7.03 (s, 1H), 7.72 (s, 2H), 7.75 (s, 1H)
138
Figure US07807701-20101005-C00157
 		CDCl3: 0.70-1.20 (m, 4H), 1.00 (m, 3H), 1.30-2.40 (m, 8H), 2.97 (m, 2H), 3.14 (m, 2H), 4.20 (s, 3H), 4.85 (s, 2H), 5.04 (s, 2H), 5.39 (s, 2H), 6.98 (brs, 1H), 6.99 (s, 1H), 7.70 (s, 2H), 7.75 (s, 1H)
139
Figure US07807701-20101005-C00158
 		CDCl3: 0.70-1.10 (m, 4H), 1.00 (m, 3H), 1.33-1.82 (m, 6H), 2.75-3.40 (m, 4H), 3.10 (d, J = 6.0 Hz, 2H), 3.28 (s, 3H), 4.18 (s, 3H), 4.82 (s, 2H), 5.08 (brs, 2H), 7.04 (s, 1H), 7.06-7.30 (m, 2H), 7.70 (s, 2H), 7.74 (s, 1H)
140
Figure US07807701-20101005-C00159
 		DMSO-d6: 0.55-0.85 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H), 1.05-1.35 (m, 4H), 1.40-1.80 (m, 4H), 2.68 (d, J = 6.6 Hz, 2H), 2.81 (q, J = 6.9 Hz, 2H), 3.36 (d, J = 6.9 Hz, 2H), 4.17 (s, 3H), 4.79 (s, 2H), 4.81 (s, 2H), 6.89 (s, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.86 (s, 2H), 7.97 (s, 1H)
TABLE 29
Example Structural Formula NMR (δ value, 300 MHz)
141
Figure US07807701-20101005-C00160
 		CDCl3: 0.65-0.95 (m, 2H), 0.95-1.25 (m, 2H), 1.06 (m, 3H), 1.25-1.95 (m, 6H), 2.38 (s, 3H), 3.05-3.70 (m, 4H), 3.35 (m, 2H), 4.19 (s, 3H), 4.96 (s, 2H), 5.34 (brs, 2H), 7.26 (s, 1H), 7.36 (brs, 1H), 7.74 (s, 3H)
142
Figure US07807701-20101005-C00161
 		DMSO-d6: 0.63-0.90 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H), 1.29 (m, 1H), 1.50 (m, 1H), 1.45-1.80 (m, 4H), 2.00 (d, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.77 (d, J = 6.6 Hz, 2H), 2.88 (q, J = 6.9 Hz, 2H), 4.17 (s, 3H), 4.77 (s, 4H), 7.14 (s, 1H), 7.16 (s, 1H), 7.78 (s, 2H), 7.93 (s, 1H)
143
Figure US07807701-20101005-C00162
 		CDCl3: 0.70-0.95 (m, 2H), 0.95-1.32 (m, 2H), 1.07 (m, 3H), 1.35-1.95 (m, 6H), 2.12 (d, J = 6.7 Hz, 2H), 2.38 (s, 3H), 3.34 (m, 2H), 3.50 (m, 2H), 4.18 (s, 3H), 4.99 (s, 2H), 5.36 (s, 2H), 7.22 (s, 1H), 7.38 (brs, 1H), 7.73 (s, 1H), 7.76 (s, 2H)
144
Figure US07807701-20101005-C00163
 		CDCl3: 0.68-0.95 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H), 1.27 (m, 1H), 1.50-1.85 (m, 7H), 2.67 (d, J = 6.5 Hz, 2H), 2.81 (q, J = 6.9 Hz, 2H), 4.17 (s, 3H), 4.67 (s, 2H), 4.81 (s, 2H), 6.92 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.62 (s, 2H), 7.73 (s, 1H)
145
Figure US07807701-20101005-C00164
 		DMSO-d6: 0.66-0.85 (m, 2H), 0.83 (t, J = 6.9 Hz, 3H), 1.04-1.22 (m, 2H), 1.29 (m, 1H), 1.60-1.82 (m, 4H), 2.00 (m, 1H), 2.66 (d, J = 6.7 Hz, 2H), 2.79 (q, J = 6.9 Hz, 2H), 4.13 (s, 3H), 4.69 (s, 2H), 4.72 (s, 2H), 6.87 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.68 (s, 1H), 7.80 (s, 1H)
TABLE 30
Example Structural Formula NMR (δ value, 300 MHz)
146
Figure US07807701-20101005-C00165
 		DMSO-d6: 0.57-0.80 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H), 1.05-1.35 (m, 2H), 1.47-1.75 (m, 4H), 2.67 (d, J = 6.6 Hz, 2H), 2.79 (q, J = 7.2 Hz, 2H), 3.11 (d, J = 6.0 Hz, 2H), 4.17 (s, 3H), 4.76 (s, 2H), 4.82 (s, 2H), 7.11 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.86 (s, 2H), 7.99 (s, 1H)
147
Figure US07807701-20101005-C00166
 		DMSO-d6: 0.60-0.90 (m, 4H), 0.84 (t, J = 6.9 Hz, 3H), 1.23 (m, 1H), 1.40-1.75 (m, 5H), 1.99 (d, J = 6.9 Hz, 2H), 2.66 (d, J = 6.6 Hz, 2H), 2.78 (q, J = 6.9 Hz, 2H), 4.17 (s, 3H), 4.76 (s, 2H), 4.82 (s, 2H), 7.11 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.86 (s, 2H), 7.98 (s, 1H)
148
Figure US07807701-20101005-C00167
 		DMSO-d6: 0.55-0.75 (m, 4H), 0.81 (t, J = 6.7 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H), 1.15 (m, 1H), 1.22 (m, 1H), 1.50-1.69 (m, 4H), 2.53-2.68 (m, 4H), 2.76 (q, J = 6.7 Hz, 2H), 3.08 (d, J = 6.1 Hz, 2H), 4.14 (s, 3H), 4.70 (s, 2H), 4.77 (s, 2H), 6.92 (s, 1H), 7.08 (s, 1H), 7.80 (s, 2H), 7.94 (s, 1H)
149
Figure US07807701-20101005-C00168
 		DMSO-d6: 0.72-1.00 (m, 2H), 0.91 (t, J = 6.9 Hz, 3H), 1.02-1.35 (m, 2H), 1.33 (m, 1H), 1.69-1.87 (m, 4H), 2.03 (m, 1H), 2.76 (d, J = 6.6 Hz, 2H), 2.86 (q, J = 6.9 Hz, 2H), 3.62 (s, 3H), 4.61 (s, 2H), 4.82 (s, 2H), 6.60 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 7.06 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.97 (s, 1H)
150
Figure US07807701-20101005-C00169
 		CDCl3: 0.60-1.80 (m, 13H), 2.12 (s, 3H), 2.60-4.00 (m, 4H), 3.05 (m, 2H), 3.84 (S, 3H), 4.16 (s, 3H), 4.17 (s, 2H), 4.87 (brs, 2H), 6.56 (brs, 1H), 7.10 (brs, 1H), 7.67 (s, 3H)
TABLE 31
Example Structural Formula NMR (δ value, 300 MHz)
151
Figure US07807701-20101005-C00170
 		CDCl3: 0.65-1.85 (m, 10H), 1.03 (m, 3H), 2.09 (m, 2H), 2.15 (s, 3H), 2.27 (s, 3H), 3.00-4.00 (m, 4H), 4.15 (s, 3H), 4.93 (s, 2H), 5.34 (s, 2H), 6.90 (s, 1H), 7.10 (s, 1H), 7.69 (s, 3H)
152
Figure US07807701-20101005-C00171
 		DMSO-d6: 0.60-0.90 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H), 1.27 (m, 1H), 1.35-1.75 (m, 5H), 1.99 (d, J = 6.6 Hz, 2H), 2.77 (d, J = 6.9 Hz, 2H), 2.88 (q, J = 6.9 Hz, 2H), 4.16 (s, 3H), 4.77 (s, 2H), 4.80 (s, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.85 (s, 2H), 7.97 (s, 1H)
153
Figure US07807701-20101005-C00172
 		DMSO-d6: 0.61-0.80 (m, 4H), 0.81 (t, J = 6.3 Hz, 3H), 1.09 (t, J = 7.4 Hz, 3H), 1.22 (m, 1H), 1.45 (m, 1H), 1.45-1.67 (m, 4H), 1.96 (d, J = 6.7 Hz, 2H), 2.52-2.67 (m, 4H), 2.76 (q, J = 6.3 Hz, 2H), 4.14 (s, 3H), 4.70 (s, 2H), 4.77 (s, 2H), 6.93 (s, 1H), 7.08 (s, 1H), 7.80 (s, 2H), 7.93 (s, 1H)
154
Figure US07807701-20101005-C00173
 		DMSO-d6: 0.66-0.83 (m, 4H), 0.71 (t, J = 7.4 Hz, 3H), 1.20-1.38 (m, 3H), 1.47 (m, 1H), 1.45-1.70 (m, 4H), 1.97 (d, J = 6.7 Hz, 2H), 2.70-2.83 (m, 4H), 4.14 (s, 3H), 4.76 (s, 2H), 4.79 (s, 2H), 7.19 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.79 (s, 2H), 7.93 (s, 1H)
155
Figure US07807701-20101005-C00174
 		CDCl3: 0.66-1.87 (m, 10H), 1.04 (m, 3H), 2.11 (s, 3H), 2.15 (m, 2H), 3.00-3.80 (m, 4H), 3.85 (s, 3H), 4.16 (s, 3H), 4.93 (s, 2H), 5.30 (s, 2H), 6.55 (s, 1H), 7.11 (s, 1H), 7.66 (s, 3H)
TABLE 32
Example Structural Formula NMR (δ value, 300 MHz)
156
Figure US07807701-20101005-C00175
 		DMSO-d6: 0.60-0.85 (m, 2H), 0.83 (m, 3H), 1.00-1.18 (m, 2H), 1.28 (m, 1H), 1.58-1.80 (m, 4H), 1.99 (m, 1H), 2.65 (m, 2H), 2.79 (m, 2H), 3.47 (m, 2H), 4.16 (s, 3H), 4.76 (s, 2H), 4.78 (s, 2H), 7.08 (s, 1H), 7.19 (s, 2H), 7.85 (s, 2H), 7.97 (s, 1H)
157
Figure US07807701-20101005-C00176
 		DMSO-d6: 0.65-0.83 (m, 4H), 0.70 (t, J = 7.4 Hz, 3H), 1.22-1.38 (m, 3H), 1.41-1.73 (m, 5H), 1.97 (d, J = 6.9 Hz, 2H), 2.30 (s, 3H), 2.68-2.83 (m, 4H), 4.14 (s, 3H), 4.73 (s, 2H), 4.75 (s, 2H), 7.12 (s, 2H), 7.75 (s, 2H), 7.91 (s, 1H)
158
Figure US07807701-20101005-C00177
 		DMSO-d6: 0.60-0.85 (m, 4H), 0.73 (t, J = 7.1 Hz, 3H), 1.15-1.38 (m, 3H), 1.40-1.73 (m, 5H), 1.99 (d, J = 6.7 Hz, 2H), 2.57-2.80 (m, 4H), 4.16 (s, 3H), 4.79 (s, 2H), 4.83 (s, 2H), 6.90 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.87 (s, 2H), 7.98 (s, 1H)
159
Figure US07807701-20101005-C00178
 		DMSO-d6: 0.70-0.98 (m, 2H), 0.91 (t, J = 6.9 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H), 1.00-1.25 (m, 2H), 1.34 (m, 1H), 1.66-1.88 (m, 4H), 2.04 (m, 1H), 2.44 (q, J = 7.5 Hz, 2H), 2.76 (d, J = 6.1 Hz, 2H), 2.88 (q, J = 6.9 Hz, 2H), 4.67 (s, 2H), 4.86 (s, 2H), 6.56 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.99 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.97 (s, 1H)
160
Figure US07807701-20101005-C00179
 		DMSO-d6: 0.67-0.90 (m, 2H), 0.86 (t, J = 6.9 Hz, 3H), 1.05-1.30 (m, 2H), 1.30 (m, 1H), 1.64-1.85 (m, 4H), 2.03 (m, 1H), 2.70 (d, J = 6.6 Hz, 2H), 2.83 (q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 4.77 (s, 4H), 6.92 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.98 (s, 1H), 8.23 (s, 1H)
TABLE 33
Example Structural Formula NMR (δ value, 300 MHz)
161
Figure US07807701-20101005-C00180
 		CDCl3: 0.70-1.00 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H), 1.10-1.50 (m, 3H), 1.70-2.00 (m, 4H), 2.10 (s, 3H), 2.19 (m, 1H), 2.74 (d, J = 6.9 Hz, 2H), 2.86 (q, J = 7.2 Hz, 2H), 4.68 (s, 2H), 4.70 (s, 2H), 4.93 (s, 1H), 5.25 (s, 1H), 6.60 (d, J = 8.7 Hz, 2H), 7.06 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.70 (s, 2H), 7.79 (s, 1H)
162
Figure US07807701-20101005-C00181
 		DMSO-d6: 0.70-0.95 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H), 1.27 (m, 1H), 1.42-1.80 (m, 5H), 2.02 (d, J = 6.9 Hz, 2H), 2.14 (s, 3H), 2.76 (d, J = 6.1 Hz, 2H), 2.87 (q, J = 6.9 Hz, 2H), 4.66 (s, 2H), 4.86 (s, 2H), 6.54 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.98 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.89 (s, 2H), 7.97 (s, 1H)
163
Figure US07807701-20101005-C00182
 		DMSO-d6: 0.62-0.84 (m, 4H), 0.83 (t, J = 6.9 Hz, 3H), 1.22 (m, 1H), 1.39-1.73 (m, 5H), 1.99 (d, J = 6.7 Hz, 2H), 2.47 (s, 3H), 2.67 (d, J = 6.1 Hz, 2H), 2.79 (q, J = 6.9 Hz, 2H), 4.73 (s, 4H), 6.90 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.85 (s, 2H), 7.98 (s, 1H)
164
Figure US07807701-20101005-C00183
 		DMSO-d6: 0.65-0.90 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H), 1.29 (m, 1H), 1.42-1.78 (m, 5H), 2.00 (d, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.50 (s, 3H), 2.76 (d, J = 6.9 Hz, 2H), 2.85 (q, J = 6.9 Hz, 2H), 4.68 (s, 4H), 7.12 (s, 1H), 7.14 (s, 1H), 7.75 (s, 2H), 7.94 (s, 1H)
165
Figure US07807701-20101005-C00184
 		DMSO-d6: 0.65-0.83 (m, 4H), 0.70 (t, J = 7.5 Hz, 3H), 1.22-1.37 (m, 3H), 1.40-1.70 (m, 5H), 1.97 (d, J = 6.7 Hz, 2H), 2.31 (s, 3H), 2.46 (s, 3H), 2.67-2.80 (m, 4H), 4.66 (s, 4H), 7.11 (s, 2H), 7.73 (s, 2H), 7.92 (s, 1H)
TABLE 34
Example Structural Formula NMR (δ value, 300 MHz)
166
Figure US07807701-20101005-C00185
 		CDCl3: 0.76 (t, J = 7.4 Hz, 3H), 0.77-0.90 (m, 4H), 1.30-1.42 (m, 4H), 1.42-1.75 (m, 5H), 2.17 (d, J = 6.4 Hz, 2H), 2.38 (s, 3H), 2.74 (d, J = 7.0 Hz, 2H), 2.77 (m, 2H), 4.19 (s, 3H), 4.62 (s, 2H), 4.79 (s, 2H), 6.92 (s, 1H), 7.25 (s, 1H), 7.57 (s, 2H), 7.70 (s, 1H)
167
Figure US07807701-20101005-C00186
 		CDCl3: 0.65-1.00 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H), 1.31 (m, 1H), 1.57-1.77 (m, 5H), 2.17 (d, J = 6.7 Hz, 2H), 2.30 (s, 3H), 2.68 (d, J = 7.0 Hz, 2H), 2.83 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 4.68 (s, 2H), 4.85 (s, 2H), 6.98 (s, 1H), 7.33 (s, 1H), 7.63 (s, 2H), 7.74 (s, 1H)
168
Figure US07807701-20101005-C00187
 		CDCl3: 0.75-1.30 (m, 4H), 1.05 (m, 3H), 1.32-1.85 (m, 6H), 2.13 (d, J = 6.5 Hz, 2H), 2.50 (s, 3H), 2.80 (s, 3H), 3.00-4.00 (m, 4H), 4.18 (s, 3H), 4.92 (s, 2H), 4.97 (s, 2H), 7.20 (s, 1H), 7.38 (s, 1H), 7.77 (s, 3H)
179
Figure US07807701-20101005-C00188
 		CDCl3: 0.70-1.00 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.36 (m, 1H), 1.45-1.85 (m, 5H), 2.12 (d, J = 6.6 Hz, 2H), 2.39 (s, 3H), 2.75 (d, J = 7.0 Hz, 2H), 2.88 (q, J = 7.0 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.20 (s, 3H), 4.63 (s, 2H), 4.80 (s, 2H), 6.93 (s, 1H), 7.26 (s, 1H), 7.59 (s, 2H), 7.72 (s, 1H)
170
Figure US07807701-20101005-C00189
 		CDCl3: 0.68-1.05 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H), 1.36 (m, 1H), 1.57-1.81 (m, 5H), 2.18 (d, J = 6.6 Hz, 2H), 2.40 (s, 3H), 2.76 (d, J = 7.0 Hz, 2H), 2.88 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 4.63 (s, 2H), 4.80 (s, 2H), 6.93 (s, 1H), 7.27 (s, 1H), 7.59 (s, 2H), 7.72 (s, 1H)
The compounds shown in Table 35 can be produced in a similar manner.
TABLE 35
Structural Formula Compound Name
Figure US07807701-20101005-C00190
 		trans-(4-{[N-(2-{[N′-(3-methyl-5- trifluoromethylbenzyl)-N′-(2-methyl-2H- tetrazol-5-yl)amino]methyl}-5-methyl-4- trifluoromethylphenyl)-N- ethylamino]methyl}cyclohexyl)acetic acid
Figure US07807701-20101005-C00191
 		trans-(4-{[N-(2-{[N′-(3-methyl-5- trifluoromethylbenzyl)-N′-(5-methyl- [1,2,4]oxadiazol-3-yl)amino]methyl}-5-methyl- 4-trifluoromethylphenyl)-N- ethylamino]methyl}cyclohexyl)acetic acid
Figure US07807701-20101005-C00192
 		ethyl cis-(4-{[N-(2-{[N′-[3,5- bis(trifluoromethyl)benzyl]-N′-(2-methyl-2H- tetrazol-5-yl)amino]methyl}-5-methyl-4- trifluoromethylphenyl)-N- ethylamino]methyl}cyclohexyl)acetate
Figure US07807701-20101005-C00193
 		{4-[2-(2-{[N-[3,5-bis(trifluoromethyl)benzyl]- N-(2-methyl-2H-tetrazol-5-yl)amino]methyl}- 5-methyl-4-trifluoromethylphenyl)butyl]- cyclohexyl}acetic acid
Figure US07807701-20101005-C00194
 		5-[2-({N-[3,5-bis(trifluoromethyl)benzyl]-N- [2-methyl-2H-tetrazol-5-yl]amino}methyl)-5- methyl-4-trifluoromethylphenoxy]heptanoic acid
Experimental Examples
The following tests were performed for the CETP activity inhibitory effect of the compound of the present invention.
Preparation of Donor Lipoprotein
Potassium bromide (KBr) was added to plasma (40 mL) of healthy subject and the mixture was adjusted to have a specific density d=1.125 g/mL. The mixture was subjected to density gradient centrifugation (227,000×g, 4° C., 17 hr) and a fraction showing a specific density of d>1.125 g/mL (HDL3 fraction) was harvested. The obtained fraction was dialyzed against PBS solution [10 mmol/L Na2HPO4; 10 mmol/L NaH2PO4; 0.15 mol/L NaCl; 1 mol/L EDTA (pH 7.4)]. Then, tritium-labeled cholesterol (37 MBq) was dissolved in 95% ethanol, gradually added to the above-mentioned HDL3 fraction with stirring and incubated at 37° C. for 18 hr. [By this operation, tritium-labeled cholesterol was esterified by the action of lecithin acyl transferase (LCAT) present on the HDL3 surface and taken up into HDL3 as tritium-labeled cholesteryl ester ([3H]CE)]. After incubation, KBr was added, the mixture was adjusted to have a specific density d=1.21 g/mL, subjected to density gradient centrifugation (227,000×g, 4° C., 17 hr) and a fraction of specific density d>1.21 g/mL was harvested. The obtained fraction was dialyzed against the aforementioned PBS solution to give HDL3 incorporating [3H]CE ([3H]CE-HDL3, specific density: 1.125<d<1.21, specific activity: 10,000 dpm/μL), which was used as a donor lipoprotein.
Experimental Example 1 Inhibitory Effect In Vitro on CETP Activity in Total Plasma
The donor lipoprotein obtained above was added to plasma of healthy subject to prepare a [3H]CE-HDL3-containing plasma (1,000 dpm/μL). The compound was dissolved in dimethyl formamide. A solution of the compound or a solvent alone (2 μL) and the [3H]CE-HDL3-containing plasma (100 μL) were added into a microtube, and this was incubated at 37° C. or 4° C. for 4 hr. After ice-cooling, TBS solution [100 μL, 20 mmol/L Tris; 0.15 mol/L NaCl (pH 7.4)] containing 1 mol/L magnesium chloride and 2% dextran sulfate was added to each microtube and the mixture was thoroughly stirred. After keeping at 4° C. for 30 min, the mixture was centrifuged (10,000×g, 4° C., 10 min), and the radioactivity in the obtained supernatant (HDL fraction) was measured with a scintillation counter. The difference in the measurement values obtained by incubation of solvent alone at 4° C. and 37° C. was taken as CETP activity, and the proportion of decrease in the difference in the measurement values of specimen was taken as percent inhibition of CETP activity. The concentration of the compound necessary for inhibiting the CETP activity by 50% was calculated as an IC50 value. The results are shown in the following.
TABLE 36
Example No. IC50 (μM) Example No. IC50 (μM)
1 0.23 2 0.08
3 0.24 4 0.18
7 0.27 8 0.63
10 0.23 11 0.63
12 0.25 13 0.58
26 0.47 27 0.58
28 0.44 33 0.56
34 0.22 35 0.35
36 0.34 37 0.80
38 0.47 39 0.88
40 0.39 41 0.51
42 0.70 43 0.55
44 0.36 45 0.49
46 0.39 51 0.41
52 0.37 53 0.70
54 0.79 55 0.77
58 0.715 59 0.43
60 0.78 63 0.64
64 0.75 65 0.29
66 0.87 67 0.26
68 0.28 69 0.34
70 0.54 71 0.44
72 0.39 73 0.19
74 0.40 75 0.41
The IC50 values in Table show average values.
TABLE 37
Example No. IC50 (μM) Example No. IC50 (μM)
76 0.29 77 0.54
78 0.32 79 0.89
80 0.43 81 0.33
82 0.59 86 0.941
89 0.69 91 0.56
92 0.19 93 0.76
96 0.31 98 0.30
99 0.53 102 0.59
103 0.43 104 0.35
105 0.60 107 0.56
108 0.25 109 0.16
111 0.19 114 0.28
115 0.09 118 0.09
119 0.13 120 0.28
121 0.23 122 0.24
127 0.37 129 0.61
131 0.17 135 0.22
137 0.14 138 0.16
140 0.12 141 0.12
142 0.06 143 0.10
The IC50 values in Table show average values.
Experimental Example 2 Inhibitory Effect Exo Vivo on CETP Activity in Total Plasma of Normal Hamster
The compound of the present invention was suspended in 0.5% methyl cellulose solution and orally administered once to a healthy hamster with a plastic gavage needle. Blood was taken at 2 or 4 hr after the administration and CETP activity in plasma was measured according to the following method.
The donor lipoprotein obtained above was added to hamster plasma (100 μL) to prepare [3H]CE-HDL3-containing plasma (ca. 1,000 dpm/μL). The [3H]CE-HDL3-containing plasma was dispensed to two microtubes by 25 μL each, and one was incubated at 37° C. and the other was incubated at 4° C. for 4 hr each. After ice-cooling, TBS solution (50 μl) containing 1 mol/L magnesium chloride and 2% dextran sulfate was added to each microtube and the mixture was thoroughly stirred. After keeping at 41° C. for 30 min, the mixture was centrifuged (10,000×g, 4° C., 20 min), and the radioactivity in the obtained supernatant (HDL fraction) was measured with a liquid scintillation counter. The radioactivity of the [3H]CE-HDL3-containing plasma was measured with a liquid scintillation counter, and taken as the total radioactivity. The transfer rate of [3H]CE was calculated from the following formula using the total radioactivity (Total count), radioactivity by 37° C. incubation (37° C. count) and radioactivity by 4° C. incubation (4° C. count) of the sample of each individual and taken as the CETP activity.
CETP activity(transfer ratio (%))={[(4° C. count)−(37° C. count)]/(Total count)}×100
The CETP activity inhibitory ratio of each compound administration group based on the CETP activity of the solvent administration group as 100% was calculated from the following formula and expressed in %.
CETP activity inhibitory ratio (%)=100−[(CETP activity of each compound administration group)/(CETP activity of solvent administration group)×100]
The results are shown in the following.
TABLE 38
CETP activity (%)
compound Dose (mg/kg) 2 (hr later) 4 (hr later)
35 30 37.8 —
36 30 33.3 —
37 30 45.4 —
38 30 79.4 —
39 30 49.6 —
40 30 59.5 —
41 30 36.0 —
89 10 77.7 —
91 10 44.7 —
92 10 46.9 —
96 10 41.1 —
98 10 43.3 —
107 10 41.9 —
108 10 53.8 —
109 10 42.8 —
115 3 — 62.1
118 3 — 55.4
142 3 — 71.6
143 3 — 42.2
154 3 — 64.2
157 3 — 80.4
158 3 — 55.6
The CETP activity inhibitory ratios in Table show average values.
Experimental Example 3 Blood HDL Cholesterol Increasing Effect in Normal Hamster
To the plasma (40 μL) obtained from the above-mentioned animal at 4 or 8 hr after the administration was added 15% polyethylene glycol solution (40 μL) and the mixture was thoroughly stirred. After keeping at room temperature for 10 min, the mixture was centrifuged (10,000×g, 4° C., 20 min) and the cholesterol content (HDL cholesterol content) of the obtained supernatant (HDL fraction) was measured. The increase ratio of the HDL cholesterol content of each compound administration group when the HDL cholesterol content of the solvent administration group as 100% was calculated from the following formula and expressed in %.
HDL cholesterol increase ratio(%)=[(HDL cholesterol content of each compound administration group/HDL cholesterol content of solvent administration group)×100]−100
The results are shown in the following.
TABLE 39
HDL cholesterol
increase content (%)
compound Dose (mg/kg) 4 (hr later) 8 (hr later)
115 3 23.3 30.7
118 3 21.1 31.7
142 3 20.3 31.9
143 3 17.0 21.3
154 3 13.3 22.4
157 3 17.9 27.1
158 3 14.8 23.7
The HDL cholesterol increase ratios in Table show average values.
Experimental Example 4 Concomitant Use Test
For the experiment, 10-week-old male Japanese white rabbits (manufactured by KITAYAMA LABES Co., Ltd.) were used. The animal was acclimated on normal food (RC-4, manufactured by Oriental Bio-Service Co.) and fasted for 24 hr and a high cholesterol food (0.25% cholesterol-added RC-4, manufactured by Oriental Bio-Service Co.) was given by 100 g/day per rabbit (preliminary feeding) for 3 days. On the next day of day 3 of preliminary feeding, blood was taken from the auricular artery before feeding, and the animals were grouped by 6 rabbits per group based on the parameters (HDL cholesterol content, total cholesterol content, triglyceride content) of plasma and body weight.
Foods were prepared (manufactured by Oriental Bio-Service Co.) by adding simvastatin (0.002%), compound (0.2%) of Example 168, or simvastatin (0.002%)+compound (0.2%) of Example 168 to a high cholesterol food, and each food was given to the grouped animals by 100 g/day per rabbit for 15 days. At 8 hr after feeding on day 15, the total blood was taken from the carotid artery under anesthesia, HDL cholesterol content, total cholesterol content and ApoA-I content in plasma were measured. The arteriosclerosis index was calculated from [(total cholesterol content-HDL cholesterol content)/HDL cholesterol content]. Furthermore, the HDL3 fraction was separated from plasma by ultracentrifugation and the cholesterol content of the fraction was measured. In Table, arteriosclerotic index, ApoA-1 content and HDL3 cholesterol content are shown based on the value of the control group as 100%.
TABLE 40
Arteriosclerotic ApoA-I content HDL3 cholesterol
group index (%) (%) content (%)
control 100 100 100
simvastatin 53 114 128
compound of 82 114 141
Example 168
Simvastatin + 37 150 170
compound of
Example 168
INDUSTRIAL APPLICABILITY
From the foregoing test results and the like, the compound and a salt thereof of the present invention have superior CETP activity inhibitory effect. Therefore, they can decrease IDL, VLDL and LDL that promote arteriosclerosis and increase HDL that acts suppressively. As a result, they are useful as prophylactic or therapeutic agents for hyperlipidemia. In addition, they are useful as prophylactic or therapeutic agents for arteriosclerotic disease and the like.
Moreover, concurrent use of the compound of the present invention with a different therapeutic agent for hyperlipidemia (statin pharmaceutical agent) is expected to promote increase in HDL cholesterol, decrease arteriosclerotic index particularly remarkably, and show extremely superior synergistic effect. Therefore, it is clear that the compound of the present invention can be used concurrently with a different pharmaceutical agent, particularly other therapeutic agents for hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension.

Claims (43)

1. A dibenzylamine compound represented by the formula (1)
Figure US07807701-20101005-C00195
wherein
R1 and R2
are the same or different and each is a halogen atom, a nitro group, a cyano group or a C1-6 alkyl group optionally substituted by halogen atoms;
R3, R4 and R5
are the same or different and each is a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted by halogen atoms, a C1-6 alkylthio group optionally substituted by halogen atoms or a C1-6 alkoxy group optionally substituted by halogen atoms, or R3 and R4 or R4 and R5 may form, together with a carbon atom bonded thereto, a homocyclic ring optionally having substituent(s) or a heterocyclic ring optionally having substituent(s);
A is
—C(R11)(R12)(R13)
(wherein R11, R12 and R13 are the same or different and each is
a hydrogen atom,
a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by phenyl group or —COOR9 (wherein R9 is a hydrogen atom or a C1-6 alkyl group)) or
a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group, C1-6 alkoxy group or phosphono group), —(CH2)q—CON(R20)(R21) (wherein R20 and R21 are the same or different and each is hydrogen atom or C1-6 alkyl group and q is 0 or an integer of 1 to 5) or —(CH2)r—COOR10 (wherein R10 is hydrogen atom or C1-6 alkyl group and r is 0 or an integer of 1 to 5)))
or
—O—C(R11)(R12)(R13) (wherein R11, R12 and R13 are as defined above);
Ring B is an aryl group or a hetercyclic residue;
R6 is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C1-6 alkoxy group, a C2-6 alkenyl group or a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or —COOR14 (wherein R14 is a hydrogen atom or a C1-6 alkyl group)); and
n is an integer of 1 to 3
or a pharmaceutically acceptable salt thereof.
2. The dibenzylamine compound of claim 1
wherein
R3, R4 and R5
are the same or different and each is a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted by halogen atoms or a C1-6 alkoxy group optionally substituted by halogen atoms, or R3 and R4 or R4 and R5 may form, together with a carbon atom bonded thereto, a homocyclic ring optionally having substituent(s) or a heterocyclic ring optionally having substituent(s);
R11, R12 and R13
are the same or different and each is a hydrogen atom, a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by phenyl group or —COOR9 (wherein R9 is a hydrogen atom or a C1-6 alkyl group) or a C4-10 cycloalkylalkyl group (wherein C4-10 cycloalkylalkyl group is optionally substituted by 1 to 3 substituents from halogen atom, nitro group, amino group, hydroxyl group, cyano group, acyl group, C1-6 alkoxy group, C1-6 alkyl group or —COOR10 (wherein R10 a hydrogen atom or a C1-6 alkyl group));
R6 is
a hydrogen atom,
a halogen atom,
a nitro group,
an amino group,
a hydroxyl group,
a cyano group,
an acyl group,
a C1-6 alkoxy group
or
a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or —COOR14 (wherein R14 is a hydrogen atom or a C1-6 alkyl group)),
or a pharmaceutically acceptable salt thereof.
3. The dibenzylamine compound of claim 2, wherein R1 is a C1-6 alkyl group substituted by a halogen atom, or a pharmaceutically acceptable salt thereof.
4. The dibenzylamine compound of claim 3, wherein R1 is a trifluoromethyl group, or a pharmaceutically acceptable salt thereof.
5. The dibenzylamine compound of claim 4, wherein ring B and (R6)n are each
Figure US07807701-20101005-C00196
Figure US07807701-20101005-C00197
wherein R60, R61 and R62 are the same or different and each is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C1-6 alkoxy group, a C2-6 alkenyl group or a C1-6 alkyl group (wherein C1-6 alkyl group is optionally substituted by hydroxyl group or —COOR14 (wherein R14 is as defined above)) or a pharmaceutically acceptable salt thereof.
6. The dibenzylamine compound of claim 5, wherein ring B and (R6)n are each
Figure US07807701-20101005-C00198
wherein R60, R61 and R62 are as defined above or a pharmaceutically acceptable salt thereof.
7. The dibenzylamine compound of claim 6, wherein ring B and (R6)n are each
Figure US07807701-20101005-C00199
wherein R60 and R61 are as defined above or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising the dibenzylamine compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A method for treating hyperlipidemia, which comprises administering a dibenzylamine compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal.
10. A method for treating arteriosclerosis, which comprises administering a dibenzylamine compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal.
11. The pharmaceutical composition of claim 8, which is used in combination with a different therapeutic agent for hyperlipidemia.
12. The pharmaceutical composition of claim 11, wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
13. The pharmaceutical composition of claim 12, wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
14. The pharmaceutical composition of claim 8, which is used in combination with a different therapeutic agent for obesity.
15. The pharmaceutical composition of claim 14, wherein the different therapeutic agent for obesity is mazindol.
16. The pharmaceutical composition of claim 8, which is used in combination with a different therapeutic agent for diabetes.
17. The pharmaceutical composition of claim 16, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
18. The pharmaceutical composition of claim 17, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
19. The pharmaceutical composition of claim 8, which is used in combination with a different therapeutic agent for hypertension.
20. The pharmaceutical composition of claim 19, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
21. The pharmaceutical composition of claim 20, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
22. The method of claim 9, which aims at the treatment of hyperlipidemia and which is used in combination with a different therapeutic agent for hyperlipidemia.
23. The method of claim 22, wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
24. The method of claim 23, wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
25. The method of claim 9, which aims at the treatment of hyperlipidemia and which is used in combination with a different therapeutic agent for obesity.
26. The method of claim 25, wherein the different therapeutic agent for obesity is mazindol.
27. The method of claim 9, which aims at the treatment of hyperlipidemia and which is used in combination with a different therapeutic agent for diabetes.
28. The method of claim 27, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
29. The method of claim 28, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
30. The method of claim 9, which aims at the treatment of hyperlipidemia and which is used in combination with a different therapeutic agent for hypertension.
31. The method of claim 30, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
32. The method of claim 31, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride; a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
33. The method of claim 10, which aims at the treatment of arteriosclerosis and which is used in combination with a different therapeutic agent for hyperlipidemia.
34. The method of claim 33, wherein the different therapeutic agent for hyperlipidemia is a statin pharmaceutical agent.
35. The method of claim 34, wherein the statin pharmaceutical agent is at least one pharmaceutical agent selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
36. The method of claim 10, which aims at the treatment of arteriosclerosis and which is used in combination with a different therapeutic agent for obesity.
37. The method of claim 36, wherein the different therapeutic agent for obesity is mazindol.
38. The method of claim 10, which aims at the treatment of arteriosclerosis and which is used in combination with a different therapeutic agent for diabetes.
39. The method of claim 38, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an α glucosidase inhibitor and an insulin sensitizer.
40. The method of claim 39, wherein the different therapeutic agent for diabetes is at least one pharmaceutical agent selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
41. The method of claim 10, which aims at the treatment of arteriosclerosis and which is used in combination with a different therapeutic agent for hypertension.
42. The method of claim 41, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a loop diuretic, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a Ca antagonist, a β blocker, an α,β blocker and an α blocker.
43. The method of claim 42, wherein the different therapeutic agent for hypertension is at least one pharmaceutical agent selected from the group consisting of a furosemide sustained-release preparation, captopril, a captopril sustained-release preparation, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandrapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, a nicardipine hydrochloride sustained-release preparation, nilvadipine, nifedipine, a nifedipine sustained-release preparation, benidipine hydrochloride, diltiazem hydrochloride, a diltiazem hydrochloride sustained-release preparation, nisoldipine, nitrendipine, manidipine hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, aranidipine, propranolol hydrochloride, a propranolol hydrochloride sustained-release preparation, pindolol, a pindolol sustained-release preparation, indenolol hydrochloride, carteolol hydrochloride, a carteolol hydrochloride sustained-release preparation, bunitrolol hydrochloride, a bunitrolol hydrochloride sustained-release preparation, atenolol, acebutolol hydrochloride, metoprolol tartrate, a metoprolol tartrate sustained-release preparation, nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, a bunazosin hydrochloride sustained-release preparation, urapidil and phentolamine mesylate.
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US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
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